Pyrimidinone-1,3-oxathiolane derivatives with antiviral activity

ABSTRACT

Compounds of formula (I) wherein R a  and R b  the same or different, are hydrogen atoms, acyl groups deriving from a lower carboxylic acid or chains of formula (a) useful as reverse transcriptase inhibitors antiviral activity are described.

The present invention relates to antiviral nucleosides and, moreparticularly, relates to 1,3-oxathiolane derivatives endowed withreverse transcriptase inhibitory activity Since the discovery of HIVvirus, responsible for AIDS, remarkable efforts have been made in theattempt of identifying an effective therapy.

Some nucleoside derivatives, such as zidovudine, zalcitabine, didanosineand stavudine (USP Dictionary of USAN and International Drug Names,1997, pages 774, 772, 228 and 669 respectively), have become of clinicaluse, each other sometimes in association.

All these drugs act as reverse transcriptase inhibitors (RT-inhibitors).

In fact, reverse transcriptase is an enzyme involved in theintracellular replication of the virus because it catalyses the DNAtranscription from the viral RNA.

Therefore, the RT-inhibitors act in a very early vital stage of theviral replication and this is the reason of their remarkable therapeuticinterest.

On the other hand, the prolonged use of RT-inhibitors used up to now intherapy is practically impossible because of the appearance ofresistance, side-effects and toxic effects mainly connected with theirlow selectivity.

Very recently,(2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone,better known with the common name lamivudine (USP Dictionary of USAN andInternational Drug Names, 1997, page 398), a compound described in theInternational patent application no. WO 91/17159 (IAF BiochemInternational Inc.) as more potent and less toxic antiviral thanzidovudine, zalcitabine, didanosine and stavudine has entered theclinical use.

Lamivudine is the levorotatory enantiomer (2R,5S) of the compound knownwith the code BCH-189 described in the European patent application no. 0382 526 (IAF Biochem International Inc.).

Notwithstanding the progress obtained in these last years in thetreatment of AIDS, the disease still has a huge medical and socialrelevance for its extreme seriousness and for its fast spread.

Therefore, there is still a very high need of new drugs endowed with analways greater efficacy and with an always minor toxicity, thenparticularly suitable for prolonged therapies too.

The International patent application no. WO 95/32200 (LaboratoireLaphal) describes derivatives of lamivudine and of BCH-189 characterisedby the presence of an acyl or arylalkoyl group deriving from a mono orbicyclic nitrogen containing heterocycle, as substituent of the aminogroup.

We have now found that by introducing a nitrogen containing chain offormula

wherein

R is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, a C₃-C₇cycloalkyl group or a group selected among

wherein q is an integer from 1 to 3; p is an integer from 1 to 4; Het isa 5 or 6 member heterocycle containing 1 or 2 heteroatoms selected amongoxygen, nitrogen and sulfur and R₃ is a hydrogen or halogen atom, atrifluoromethyl group or a C₁-C₃ alkoxy group;

R₁ and R₂, the same or different, are hydrogen atoms,phenylalkoxycarbonyl groups having from 1 to 3 carbon atoms in thealkoxy moiety, C₂-C₆ alkoxycarbonyl groups or C₂-C₆ alkylcarbonylgroups;

W is a single bond, an oxygen atom or a —CH(Alk)— group wherein Alk is alinear or branched C₁-C₃ alkyl group;

r is 0 or 1;

n=x when r is 0

n=y when r is 1;

x is an integer from 1 to 6;

y is an integer from 2 to 7;

m is an integer from 2 to 7;

onto a function of lamivudine which can be acylated, the antiviralactivity of lamivudine is remarkable strengthened.

Therefore, object of the present invention are compounds of formula

wherein

R_(a) and R_(b), the same or different, are hydrogen atoms, acyl groupsderiving from a lower carboxylic acid or chains of formula

wherein

R is a hydrogen atom, a linear or branched C₁-C₆ alkyl group, a C₃-C₇cycloalkyl group or a group selected among

wherein q is an integer from 1 to 3; p is an integer from 1 to 4; Het isa 5 or 6 member heterocycle containing 1 or 2 heteroatoms selected amongoxygen, nitrogen and sulfur and R₃ is a hydrogen or halogen atom, atrifluoromethyl group or a C₁-C₃ alkoxy group;

R₁ and R₂, the same or different, are a hydrogen atom, aphenylalkoxycarbonyl group having from 1 to 3 carbon atoms in the alkoxymoiety, a C₂-C₆ alkoxycarbonyl group or a C₂-C₆ alkylcarbonyl group;

W is a single bond, an oxygen atom or a —CH(Alk)— group wherein Alk is alinear or branched C₁-C₃ alkyl group;

r is 0 or 1;

n=x when r is 0

n=y when r is 1;

x is an integer from 1 to 6,

y is an integer from 2 to 7;

m is an integer from 2 to 7;

provided that at least one of R_(a) and R_(b) is different from ahydrogen atom or from an acyl group deriving from a lower carboxylicacid; tautomeric forms and pharmaceutically acceptable salts thereof.

The compounds of formula I are lamivudine derivatives (prodrugs) whichrelease lamivudine into the organism but are endowed with antiviralactivity, as reverse transcriptase inhibitors, more potent thanlamivudine on lymphocytes and, particularly, on macrophages.

Notwithstanding in the literature, as already reported, the termlamivudine more commonly refers to the levorotatory enantiomer (2R-cis)of 4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone,while the corresponding racemate is referred to as the code BCH- 189,for the sake of simplicity in the present context, if not otherwisespecified, the term lamivudine refers to the compound of formula

in the form of stereoisomeric mixture as well as in the form of one ofthe possible isomers thereof.

The compounds of formula I, object of the present invention, can have asingle chain, bound to the OH function or to the NH₂ function oflamivudine, or two chains bound to the OH function and to the NH₂function of lamivudine. Specific examples of compounds of formula I are:

wherein R, R₁, R₂, W, n, m and r have the already reported meanings;R′_(a) and R′_(b) are hydrogen atoms or an acyl group deriving from-alower carboxylic acid.

In the present description, when not otherwise specified, the termlinear or branched C₁-C₆ alkyl refers to a group selected among methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, neopentyl, isopentyl, tert-pentyl, sec-pentyl, hexyl andisohexyl; the term C₂-C₇ cycloalkyl refers to a group selected amongcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloeptyl; theterm C₁-C₃ alkoxy refers to a group selected among methoxy, ethoxy,propoxy and isopropoxy; the term C₂-C₆ alkoxycarbonyl refers to a groupselected among methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl (also referred to as BOC), sec-butoxycarbonyl andpentoxycarbonyl; the term C₂-C₆ alkylcarbonyl refers to a group selectedamong acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl and hexanoyl; the term acyl deriving from a lower carboxylicacid refers to a group selected among acetyl, propionyl, butyryl andisobutyryl, the term 5 or 6 member heterocycle containing 1 or 2heteroatoms selected among oxygen, nitrogen and sulphur refers to aheterocycle selected among thiophene, furan, pyrane, pyrrole, imidazole,pyrazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine,pyrimidine and pyridazine, optionally benzocondensed.

A class of preferred compounds of formula I is represented by thecompounds having, the (2R,5S) configuration of lamivudine.

Another class of preferred compounds is represented by the compounds offormula I-A.

Within this class, preferred compounds are the compounds wherein R₁ andR₂ are different from hydrogen and, more preferably, are C₂-C₆alkoxycarbonyl groups such as, for example, ethoxycarbonyl ortert-butoxycarbonyl groups.

Still more preferred are the compounds of formula I-A wherein R₁ and R₂are different from hydrogen and R is a group of formula

wherein R₃ and q have the already reported meanings.

Another class of particularly interesting compounds is represented bythe compounds of formula I wherein R is a group of formula

wherein q is 1 and R₃ has the already reported meanings.

The compounds of formula I wherein W is a single bond; R is a group offormula

in which q is 1;

R₃ is a hydrogen atom or a trifluoromethyl group are particularlypreferred.

Still more preferred are the compounds of formula I wherein W is asingle bond; R is a group of formula

q is 1;

R₃ is a hydrogen atom or a trifluoromethyl group;

n is an integer from 4 to 6 and m is selected among 4 and 5.

The preparation of the compounds of formula I, object of the presentinvention, can be carried out by acylation according to conventionaltechniques.

In particular, lamivudine is acylated by reaction with a compound offormula

wherein R, R₁, R₂, n, m and W have the already reported meanings and R₄is an OH group or a suitable leaving group when W is different fromoxygen or R₄ is a suitable leaving group when W is oxygen.

In general, when the acylation is carried out by directly using acompound of formula II wherein R₄ is OH, also a condensation agent suchas dicyclohexylcarbodiimide (DDC),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), carbonyl-1,1′-diimidazole (CDI) or pivaloyl chloride/LiCl isused.

The intermediate of formula II is generally used in a protected form.

The term protected from has to be intended in its broadest meaning. Infact, protected intermediate refers to an intermediate already bearingthe R₁ and R₂ functions foreseen for the final compound on the aminogroups as well as bearing R₁ and R₂ functions which will be removed toobtain the compounds of formula I wherein R₁ and R₂ are hydrogen atomsor to obtain, after further finctionalization, the compounds of formulaI wherein R₁ and R₂ are different from hydrogen and particularly areacyl groups.

The direct acylation of lamivudine with a compound of formula II,according to what already reported, leads to the obtainment of a mixtureof compounds of formula I-A, I-B and I-C which can be then separatedwith conventional techniques, for example by chromatography.

By suitably changing the operative conditions it will be possible toselectively acylate only one of the OH or NH₂ lamivudine functions, soobtaining the compounds of formula I-A or I-B.

For the preparation of the compounds of formula I-A, for example, theselective protection of the NH₂ function of lamivudine, the acylationwith a compound of formula II and optionally the removal of theprotecting group can be carried out. The selective protection of the NH₂function of lamivudine can be carried out by using acyl groups,preferably acetyl, or through the formation of imines.

In this last case, after acylation of the OH group with a suitablecompound of formula II according to what already reported, theprotecting group will be removed by treatment with diluted acids.

Similarly, for the preparation of the compounds of formula I-B the OHfunction of lamivudine can be selectively protected.

Examples of suitable protecting groups of the OH function are silylderivatives, such as tert-butyldimethylsilyl, tert-butyidiphenylsilyl ortrimethylsilyl, which can then be removed by treatment with dilutedacids or with tetrabutylammoniumfluoride.

The compounds of formula II wherein r=0 are known or can be preparedwith known methods.

For example, the compounds of formula II wherein r=0, W is differentfrom oxygen, R and R₁ are hydrogen atoms are generally commerciallyavailable.

The preparation of compounds of formula II wherein r=0, W is differentfrom oxygen and one or both R and R₁ are different from hydrogen ispreferably carried out starting from the corresponding aminoalcohols offormula

wherein x has the already reported meanings and W₁ is a single bond or agroup —CH(Alk)— wherein Alk is a linear or branched C₁-C₃ alkyl group;

a) by direct alkylation or by reaction with a suitable aldehyde followedby reduction of the imine

and/or

b) by acylation with a suitable acylating agent

so obtaining the compounds of formula

wherein x and W₁ have the already reported meanings, one or both R andR₁ are different from hydrogen.

The corresponding compounds of formula II wherein r=0 can be thenobtained by the aminoalcohols of formula III or IV.

For example, by oxidation of the alcoholic function according toconventional techniques the compounds of formula

wherein R, R₁, W₁ and x have the already reported meanings will beobtained.

The selected oxidation conditions will depend on the eventual presenceof other oxidizable functions in the molecule.

Preferably, the oxidation is carried out by using pyridinium dichromateor TEMPO/NaOCl as oxidising agents.

Instead, the compounds of formula II wherein r=0 and W is an oxygen atomare prepared from the compounds of formula

wherein R, R₁ and x have the already reported meanings;

by reaction with a suitable carbonyl derivative of formula (R₄)₂COwherein R₄ is a suitable leaving group, preferably an imidazol-1-ylgroup, so obtaining the compounds of formula

wherein R, R₁, R₄ and x have the already reported meanings.

The compounds of formula II wherein r=1 are prepared starting from thecompounds of formula III or IV wherein W₁ is a single bond, according tothe following synthetic scheme.

wherein R, R₁, R₂, x, y, m and W₁ have the already reported meanings andA is an activating group, preferably mesyl or a tosyl.

The aminoalcohol (IVb) is suitably activated to be condensed with anaminoalcohol of formula III.

The activation can be carried out by reaction with a suitable sulfonylhalide, for example tosyl or mesyl chloride, obtaining the correspondingcompound of formula V which by condensation with the aminoalcohol III,directly gives the intermediate VII. Alternatively, the activation iscarried out by oxidation to the corresponding aldehyde VI which is firstcondensed with the aminoalcohol III giving an imine and which is thendirectly reduced obtaining the compound VII.

The eventual protection of the intermediate VII followed by theoxidation according to what already reported enables to obtain thecompounds of formula IIc.

Also the compounds of formula II wherein r=1 and W is an oxygen atom areprepared from the corresponding compounds of formula

wherein R, R₁, R₂, y and m have the already reported meanings;

in a very similar way to that reported for obtaining the compounds offormula IIb, so giving the compounds of formula

wherein R, R₁, R₂, R₄, y and m have the already reported meanings.

The synthesis of the compounds of formula I, object of the presentinvention, is illustrated in more details in the following scheme, withparticular reference to the preparation of the compounds of formula I-Awherein W is a simple bond and R is a group of formula

wherein R₃ and q have the already reported meanings.

wherein R₁, R₂, R₃, R′_(b), q, x, y, m and n have the already reportedmeanings.

The condensation of the aminoalcohol 1 with the aldheyde 2, followed bythe reduction of the intermediate imine carried out direct in situ orafter isolation, gives the alcohol 3 which is protected, preferably byfunctionalization with an alkoxycarbonyl or phenylalkoxycarbonyl group,to obtain intermediate 4.

The intermediate 4 is oxidised to the corresponding carboxylicderivative 5 which can be used for the acylation of the optionallyprotected lamivudine.

Alternatively, the protecting group R₁ of compound 5 can be removedaccording to conventional techniques and the resultant compound offormula 5 wherein R₁=H can be acylated with acyl halides, to obtain thecompounds of formula 5 wherein R₁ is an acyl group.

The intermediate 4 can also be used for the preparation of the compoundsof formula 10 (II, r=1 ).

In such a case, the intermediate 4 is suitably activated (compound 6 or7) according to what already reported to be condensed with anaminoalcohol of formula 1′.

The resultant compound 8, after protection of the secondary aminofunction is oxidised.

Then, the compound 10 is used in a very similar way to that alreadydescribed for the compound 5 for direct acylating lamivudine or forobtaining the corresponding compounds of formula 10 wherein R₁ and R₂are acyl groups.

Alternatively, the compounds of formula 10 can also be prepared byoxidation of the corresponding compounds of formula 9 wherein R₁=R₂=H,described in the International patent application no. WO 96/18633 in thename of the same Applicant, so obtaining the compounds of formula 10wherein R₁=R₂ =H or by functionalization of the amino functions andoxidation, so obtaining the compounds of formula 10 wherein R₁ and R₂are different from hydrogen.

The compounds of formula I, object of the present invention, arelamivudine derivatives endowed with a remarkable antiviral activity onlimphocitic cells and in particular on macrophagic cells as reversetranscriptase inhibitors.

It is worth underlining that the antiviral activity of the compounds offormula I is generally higher than that of lamivudine, in some cases upto 1000 times more potent. Furthermore, the compounds object of thepresent invention are also active on HIV strains resistant to the bestknown RT-inhibitors.

The compounds of formula I, object of the present invention, differ fromlamivudine for a higher selectivity index toward macrophages.

The so significantly higher activity and selectivity data have led tomake the hypothesis that the compounds of formula I, object of thepresent invention, besides being lamivudine pro-drugs are also involvedin a mechanism of action, for example a transport through the cellmembranes of lymphocytes and of macrophages, which there is not in thecase of lamivudine.

It is worth underlining that from a therapeutic viewpoint, the potentantiviral activity as well as the remarkable selectivity represent animportant advantage of the compounds object of the present invention incomparison with the RT-inhibitors class, and in particular, withlamivudine.

In fact, it is known that macrophages are extremely important and, atthe same time, difficulty reachable targets in the treatment of HIVinfections.

It is also known that macrophages have a role of “reservoir” for HIVvirus in humans (J. Embretson et al., Nature, vol. 362, pages 359-362,1993).

The possibility of targetting the macrophages with a compound having aso potent antiviral activity enables to act effectively on the virusalso during the asympthomatic phase of the disease when the virus isstill silent and stored into the macrophages.

The antiviral activity of the compounds of formula I, object of thepresent invention, was evaluated on the MT4 human lymphocytes infectedby HIV-1 BRU strain and on fresh human macrophages infected by themacrophage-trophic HIV-1 PAR strain.

Both kinds of experiment were carried out following conventionally usedmethods for the evaluation of reverse transcriptase inhibitors and arepredictive of the in vivo anti-HIV activity.

For the use in therapy, the compounds of formula I can be administeredby oral or parenteral route with suitable pharmaceutical forms.

For the parenteral administration the compounds of formula I can, forexample, be used as aqueous solutions or suspensions.

For the oral administration the compounds of formula I can be formulatedin solid compositions, such as for example tablets, capsules,granulates, or in liquid compositions, such as solutions andsuspensions.

Therefore, a further object of the present invention are pharmaceuticalcompositions containing one or more compounds of formula I in admixturewith a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier will depend on the selected kindof composition and will be made by one or more excipients suitable forthe pharmaceutical use such as, for example, disintregants, diluents,surfacting agents, colouring agents, flavouring agents, bufferingagents, preservatives, etcetera.

The pharmaceutical compositions object of the present invention can alsocontain one or more compounds of formula I in association with one ormore known antivirals such as zidovudine, zalcitabine, didanosine andstavudine.

The therapeutic dose or the compounds of formula I will chance dependingon the administration route and on the patient condition but will begenerally from 50 mg and 300 mg, divided into one or two dailyadministrations (bis in diem=b.i.d.).

In order to better illustrate the present invention the followingexamples are now given.

Abbreviations and symbols used in the examples

Starting compounds: 1a = 1′a 6-aminohexan-1-ol 1b = 1′b5-aminopentan-1-ol 1c = 1′c 4-aminobutan-1-ol 1d = 1′d3-aminopropan-1-ol 1e = 1′e 2-aminoethanol 2a benzaldheyde 2b3-trifluoromethylbenzaldheyde 2c 2-trifluoromethylbenzaldheyde 2d4-methoxybenzaldheyde Reagents: BOC₂O di-tert-butyl-dicarbonate TEMPO2,2,6,6-tetramethyl-1-piperidinyloxy free radical Aliquat ®tricaprilylmethylammonium chloride TsCl tosyl chloride Et₃Ntriethylamine CDI carbonyl-1,1′-diimidazole BOP(benzotriazol-1-yloxy)tris(dimethylamino)fosfonium hexafluorofosfateSolvents: DMF N.N-dimethylformamide Et₂O ethyl ether AcOEt ethyl acetateOthers: Ts tosyl BOC tert-butoxycarbonyl Ac acetyl Piv pivaloyl Bzbenzyl Ph fenyl Et ethyl t.Bu tert-butyl

Part A—Synthesis of the Side Chains EXAMPLE 1A

Preparation of the compounds of formula 3

Method A

To 1 equivalent of aminoalcohol 1 dissolved in water 1.1 equivalents ofaldehyde 2 dissolved in Et₂O were added. The mixture was kept understirring overnight at room temperature. After extraction with Et₂O, theorganic phase was dried on Na₂SO₄ and evaporated to yield an oilyresidue. The resultant imine, characterised by TLC, was used in thesubsequent step without further purifications.

A solution of NaBH₄ in ethanol at 0° C. was added to 1 equivalent of theresultant crude imine dissolved in ethanol. The mixture was kept understirring for 2 hours at 0° C. and for further 2 hours at roomtemperature. After evaporation of ethanol, the residue was washed withwater and extracted with AcOEt. The organic phase was dried on Na₂SO₄and evaporated. The residue was purified by column chromatography.

Method B

To 1 equivalent of aminoalcohol 1 in ethanol, in the presence of 3 Åmolecular sieves, 1 equivalent of aldehyde 2 was added and the mixturewas kept under stirring fro 2.5 hours. After filtration of the molecularsieves, NaBH₄ was added portionwise to the resultant solution, understirring under nitrogen atmosphere and by keeping the temperature at15-20° C. After 1.5 hours, the solvent was evaporated under reducedpressure and the residue was taken up with water.

After extraction with Et₂O, the organic phases were washed with asolution of NaCl and dried on Na₂SO₄.

The solvent was evaporated under reduced pressure.

The following compounds of formula 3 were obtained:

6-Phenylmethylamino-hexan-1-ol (3a)

(R₃=H, q=1, x=5) from 1a and 2a (methods A and B).

Rf=0.2 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (200 MHz, CDCl₃): 7.35-7.18 (m, 5H, Ar); 3.75 (s, 2H, CH ₂ —Ar);3.60 (t, 2H, CH ₂OH); 2.60 (t, 2H, N—CH₂); 1.65 (bs, 1H, OH); 1.60-1.30[m, 8H, CH₂—(CH ₂)₄—CH₂].

6-(3-Trifluoromethylphenyl)methylamino-hexan-1-ol (3b)

(R₃=3-CF₃, q=1, x=5) from 1a and 2b (method A).

Rf=0.35 (CH₂Cl₂:CH₃OH=9:1)

6-(2-Trifluoromethylphenyl)methylamino-hexan-1-ol (3c)

(R₃=2-CF₃, q=1, x=5) from 1a and 2c (method A).

Rf=0.30 (CH₂Cl₂:CH₃OH=9:1)

5-Phenylmethylamino-pentan-1-ol (3d)

(R₃=H, q=1, x=4) from 1b and 2a (methods A and B).

Rf=0.40 (CH₂Cl₂:CH₃OH=8.5:1.5)

¹H-NMR (200 MHz, CDCl₃): 7.35-7.18 (m, 5H, Ar); 3.73 (s, 2H, CH ₂ —Ar);3.55 (t, 2H, CH ₂OH); 2.61 (t, 2H, N—CH₂); 2.00 (bs, 1H, OH); 1.60-1.30[m, 6H, CH₂—(CH ₂)₃—CH₂].

4-Phenylmethylamino-butan-1-ol (3e)

(R₃=H, q=1, x=3) from 1c and 2a (method B).

¹H-NMR (200 MHz, CDCl₃): 7.35-7.18 (m, 5H, Ar); 3.73 (s, 2H, CH ₂ —Ar);3.57-3.52 (m, 2H, CH ₂OH); 3.50 (bs, 1H, OH); 2.70-2.62 (m, 2H, N—CH₂);1.71-1.53 [m, 4H, CH₂—(CH ₂)₂—CH₂].

3-Phenylmethylamino-propan-1-ol (3f)

(R₃=H, q=1, x=2) from 1d and 2a (method B).

¹H-NMR (200 MHz, CDCl₃): 7.37-7.20 (m, 5H, Ar); 3.33-3.28 (m, 2H, CH₂OH); 3.28 (s, 2H, CH ₂ —Ar); 2.45 (bs, 1H, OH); 2.43-2.38 (m, 2H,N—CH₂); 1.78-1.65 [m, 2H, CH₂—CH ₂—CH₂].

EXAMPLE 2A

Preparation of the compounds of formula 4

Method A

To 1 equivalent of compound of formula 3, prepared as described inexample 1A, dissolved in CH₂Cl₂, 1.1 equivalents of BOC₂O in CH₂Cl₂ wereadded at 0° C. The mixture was kept under stirring for 3 hours at 0° C.and then for further 4 hours at room temperature. After evaporation ofthe solvent, the isolated residue was used without further purification.

Method B

BOC₂O dissolved into a little dioxane was added dropwise to 1 equivalentof compound of formula 3, prepared as described in example 1A, dissolvedin a 2:1 dioxane-water mixture, under stirring at 0° C.

The reaction mixture was brought to room temperature and after 2.5 hoursthe solution was concentrated by evaporating dioxane under reducedpressure.

After extraction with AcOEt, drying on Na₂SO₄ and filtration, thesolvent was evaporated under reduced pressure.

The crude was purified by flash chromatography on silica.

The following compounds of formula 4 were obtained:

6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexan-1-ol (4a)

(R₃=H, q=1, x=5, R₁=BOC) from 3a (methods A and B).

Rf=0.6 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 7.37-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂ —Ar); 3.63-3.52(m, 2H, CH ₂OH); 3.25-3.03 (m, 2H, N—CH₂); 1.60-1.20 [m, 17H, CH₂—(CH₂)₄—CH₂ and t.Bu].

6-[N-(N-tert-Butoxycarbonyl-3-trifluoromethylphenyl)methyl-amino]-hexan-1-ol(4b)

(R₃=3-CF₃, q=1, x=5, R₁=BOC) from 3b (method A).

Rf=0.61 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 1.26-1.68 (m, 17H, 4CH₂ and t.Bu); 3.20 (bs, 2H, CH₂N);3.60 (q, 2H, J₁=6.1 Hz, J₂=11.3 Hz, CH₂O); 4.44 (bs, 2H, CH₂Ph);7.40-7.47 (m, 4H, H arom.).

6-[N-(N-tert-Butoxycarbonyl-2-trifluoromethyl-phenyl)methyl-amino]-hexan-1-ol(4c)

(R₃=2-CF₃, q=1, x=5, R₁=BOC) from 3c (method A).

Rf=0.36 (CH₂Cl₂:CH₃OH=9.5:0.5)

5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentan-1-ol (4d)

(R₃=H, q=1, x=4, R₁=BOC) from 3d (methods A and B).

Rf=0.5 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 7.37-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂ —Ar); 3.64-3.52(m, 2H, CH ₂OH); 3.27-3.05 (m, 2H, N—CH₂); 1.63-1.20 [m, 6H, CH₂—(CH₂)₃—CH₂]; 1.45 (s, 9H, t.Bu).

4-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-butan-1-ol (4e)

(R₃=H, q=1, x=3, R₁=BOC) from 3e (method B).

¹H-NMR (CDCl₃): 7.37-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂ —Ar); 3.65-3.55(m, 2H, CH ₂OH); 3.30-3.10 (m, 2H, N—CH₂); 1.63-1.45 [m, 4H, CH₂—(CH₂)₂—CH₂]; 1.47 (s, 9H, t.Bu).

3-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-propan-1-ol (4f)

(R₃=H, q=1, x=2, R₁=BOC) from 3f (method B).

¹H-NMR (CDCl₃): 7.37-7.15 (m, 5H, Ar); 4.38 (s, 2H, CH ₂ —Ar); 3.58-3.50(m, 2H, CH ₂OH); 3.40-3.30 (m, 2H, N—CH₂); 3.10 (bs, 1H, OH); 1.70-1.55(m, 2H, CH₂—CH ₂—CH₂); 1.40 (s, 9H, t.Bu).

2-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-ethanol (4g)

(R₃=H, q=1, x=1, R₁=BOC) from 2-Phenylmethylamino-ethanol (method A),commercially available.

Rf=0.40 (CH₂Cl₂:CH₃OH=9.5:0.5)

EXAMPLE 3A

Preparation of the compounds of formual 5 (II—r=0)

A solution containing 1 equivalent of a compound of formula 4, preparedas described in example 2A, a catalytic amount of TEMPO, a catalyticamount of Aliquat®, a catalytic amount of KBr, 1 portion of a saturatedNaHCO₃ solution and 3 portions of CH₂Cl₂ at 0° C. was prepared. Asolution of NaClO (pH=8) was added to the solution at 0° C. Aliquots ofNaClO solution were added in a 5 hour period up to the disappearance ofthe starting compound. After 5 hours at room temperature, a 1N NaOHsolution was added up to pH 12. The mixture was kept under stirring for2 hours and then the pH was brought to 4 by addition of a 1N HClsolution. The resulting mixture was extracted with AcOEt (3 times). Theorganic phases were dried on Na₂SO₄ and, after evaporation, an oil whichwas purified by column or thin layer chromatography was obtained.

The following compounds of formula 5 were obtained:

6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexanoic acid (5a)

(R₃=H, q=1, x=5, R₁=BOC) from 4a.

Rf=0.53 (CH₂Cl₂:AcOEt=6:4)

¹H-NMR (200 MHz, CDCl₃): 7.35-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂ —Ar);3.25-3.05 (m, 2H, CH₂—N); 2.30 (t, 2H, CH ₂—COOH); 1.70-1.20 [m, 15H,CH₂—(CH ₂)₃—CH₂ and t.Bu].

6-[N-tert-Butoxycarbonyl-N-(3trifluoromethylphenyl)methyl-amino]-hexanoicacid (5b)

(R₃=3-CF₃, q=1, x=5, R₁=BOC) from 4b.

Rf=0.47 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 1.15-1.43 (m, 15H, 3CH₂ and t.Bu); 2.17 (bs, 2H, CH₂CO);3.14 (bs, 2H, CH₂N); 4.49 (bs, 2H, CH₂Ph); 7.36-7.66 (m, 4H, H arom.).

6-[N-tert-Butoxycarbonyl-N-(2-trifluoromethylphenyl)methyl-amino]-hexanoicacid (5c)

(R₃=2-CF₃, q=1, x=5, R₁=BOC) from 4c.

Rf=0.40 (CH₂Cl₂:CH₃OH=9:1)

5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentanoic acid (5d)

(R₃=H, q=1, x=4, R₁=BOC) from 4d.

¹H-NMR (200 Mhz, CDCl₃): 7.37-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂ —Ar);3.25-3.07 (m, 2H, CH₂—N); 2.48-2.25 (m, 2H, CH ₂—COOH); 1.70-1.37 [m,13H, CH₂—CH ₂—CH₂ and t.Bu).

4-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-butanoic acid (5e)

(R₃=H, q=1, x=3, R₁=BOC) from 4e.

¹H-NMR (200 MHz, CDCl₃): 8.90 (bs, COOH); 7.36-7.15 (m, 5H, Ar); 4.41(s, 2H, CH ₂ —Ar); 3.33-3.10 (m, 2H, CH₂—N); 2.38-2.25 (m, 2H, CH₂—COOH); 1.90-1.70 (m, 2H, CH₂—CH ₂—CH₂]; 1.45 (s, 9H, t.Bu).

N-tert-Butoxycarbonyl-N-phenylmethylaminoacetic acid (5g)

(R₃=H, q=1, x=1, R₁=BOC) from 4g.

Rf=0.40 (hexane:AcOEt=1:1)

¹H-NMR (CDCl₃): 1.25 (m, 9H, t.Bu), 3.65 (d, 2H, CH₂N); 4.30 (d, 2H,CH₂Ph); 6.95-7.15 (m, 5H, H arom.); 9.85 (bs, 1H, OH).

EXAMPLE 4A

Preparation of the compounds of formula 6

To 1 equivalent of a compound of formula 4, prepared as described inexample 2A, 1.1 equivalents of recrystallized TsCl, dissolved in Et₂Owere added. A large excess of Et₃N (30 equivalents) was added to thismixture.

The mixture was kept under stirring overnight at room temperature andfor further 2 hours under reflux. After cooling, the mixture wasevaporated, the residue was washed with water and extracted with CH₂Cl₂.After drying on Na₂SO₄ and evaporation, the residue was purified byflash-chromatography.

The following compounds of formula 6 were obtained:

6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexyl-4-toluene sulfonate(6a)

(R₃=H, q=1, x=5, R₁=BOC, A=Ts) from 4a.

Rf=0.5 (AcOEt:hexane=1:1)

6-[N-tert-Butoxycarbonyl-N-(2-trifluoromethylphenyl)methyl-amino]-hexyl-4-toluenesulfonate(6c)

(R₃=2-CF₃, q=1, x=5, R₁=BOC, A=Ts) from 4c.

5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentyl-4-toluene sulfonate(6d)

(R₃=H, q=1, x=4, R₁=BOC, A=Ts) from 4d.

Rf=0.12 (AcOEt:hexane=1:9)

EXAMPLE 5A

Preparation of the compounds of formula 7

A catalytic amount of TEMPO and an aqueous solution of KBr were added to1 equivalent of a compound of formula 4, prepared as described inexample 2A, dissolved in CH₂Cl₂.

The reaction mixture was cooled at 0° C. and a solution of NaClO at pH8.7 was slowly added under stirring.

The phases were extracted several times with CH₂Cl₂, washing the organicextract with water.

The organic phases were dried on Na₂SO₄.

After filtration the solvent was evaporated under reduced pressure.

The following compounds of formula 7 were obtained:

5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentanal (7d)

(R₃=H, q=1, x=4, R₁=BOC) from 4d.

¹H-NMR (CDCl₃): 9.70 (bs, 1H, CHO); 7.37-7.15 (m, 5H, Ar); 4.40 (s, 2H,CH ₂ —Ar); 3.25-3.05 (m, 2H, N—CH₂); 2.45-2.33 (m, 2H, CH₂—COO);1.61-1.36 [m, 13H, CH₂—(CH ₂)₂—CH₂ and t.Bu).

4-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-butanal (7e)

(R₃=H, q=1, x3, R₁=BOC) from 4e.

¹H-NMR (CDCl₃): 9.21 (t, 1H, CHO); 7.37-7.15 (m, 5H, Ar); 4.40 (s, 2H,CH ₂ —Ar); 3.28-3.10 (m, 2H, N—CH₂); 2.47-2.32 (m, 2H, CH ₂—CHO);1.90-1.73 (m, 2H, CH₂—CH ₂—CH₂]; 1.47 (s, 9H, t.Bu).

3-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-propanal (7f)

(R₃=H, q=1, x=2, R₁=BOC) from 4f.

¹H-NMR (CDCl₃): 9.70 (s, 1H, CHO); 7.35-7.15 (m, 5H, H arom.); 4.41 (s,2H, CH ₂ —Ar); 3.55-3.40 (m, 2H, CH ₂—OH); 2.70-2.50 (m, 2H, CH ₂—CHO);1.45 (m, 9H, t.Bu).

EXAMPLE 6A

Preparation of the compounds of formula 8

Method A

To 1 equivalent of a compound of formula 6, prepared as described inexample 4A, dissolved in anhydrous DMF 1.1 equivalents of anaminoalcohol 1′ and 5 equivalents of K₂CO₃ were added. The solution washeated at 100° C. for 6 hours. After filtration, DMF was evaporatedunder vacuum and the residue was washed with water and extracted withAcOEt. After drying on Na₂SO₄ and evaporation, the residue was purifiedby flash-chromatography.

Method B

To 1 equivalent of an aminoalcohol 1′ in ethanol, in the presence of 3 Åmolecular sieves, 1 equivalent of an aldehyde 7, prepared as describedin example 5A, was added and the mixture was kept under stirring for 2.5hours. After filtration of the molecular sieves, NABH₄ was addedportionwise to the resultant solution under stirring, under nitrogenatmosphere and by keeping the temperature at 15-20° C. After 1.5 hours,the solvent was evaporated under reduced pressure and the residue wastaken with water.

After extraction with Et₂O, the organic phases were washed with a NaClsolution and dried on Na₂SO₄.

The solvent was evaporated under reduced pressure.

The following compounds of formula 8 were obtained:

6-[6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexylamino]-hexan-1-ol(8a)

(R₃=H, q=1, y=6, m=5, R₁=BOC) from 6a and 1′a.

Rf=0.35 (CH₃OH)

6-[6-[N-tert-Butoxycarbonyl-N-(2-trifluoromethylphenyl)methylamino]-hexylamino]-hexan-1-ol(8b)

(R₃=2-CF₃, q=1, y=6, m=5, R₁=BOC) from 6c and 1a.

6-[5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentylamino]-hexan-1ol(8c)

(R₃=H, q=1, y=5, m=5, R₁=BOC) from 6d and 1′a and from 7d and 1′a.

Rf=0.21 (AcOEt:CH₃OH=1:1)

¹H-NMR (CDCl₃): 7.35-7.15 (m, 5H,Ar); 4.39 (s, 2H, CH ₂ —Ar); 3.61 (t,2H, CH ₂—OH); 3.25-3.05 (m, 2H, N—CH₂); 2.60-2.48 (m, 4H, CH ₂—NH—CH ₂);1.60-1.20 [m, 23H, CH₂—(CH ₂)₃—CH₂, N—CH₂—(CH ₂)₄—CH₂ and t.Bu].

5-[5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentylamino]-pentan-1-ol(8d)

(R₃=H, q=1, y=5, m=4, R₁=BOC) from 6d and 1′b and from 7d and 1′b.

Rf=0.23 (AcOEt: CH₃OH=1:1)

¹H-NMR (CDCl₃): 7.33-7.13 (m, 5H,Ar); 4.39 (s 2H, CH ₂—Ar); 3.65-3.55(m, 2H, CH₂—O); 3.23-3.05 (m, 2H, Ar—CH₂—N—CH ₂); 2.61-2.50 (m, 4H, CH₂—NH—CH ₂); 1.65-1.20 [m, 21H, CH₂—(CH ₂)₃—CH₂, N—CH₂—(CH ₂)₃—CH₂ andt.Bu].

5-[6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexylamino]-pentan-1-ol(8e)

(R₃=H, q=1, y=6, m=4, R₁=BOC) from 6a and 1′b.

6-[3-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-propylamino]-hexan-1-ol(8f)

(R₃=H, q=1, y=3, m=5, R₁=BOC) from 7f and 1′a.

¹H-NMR (CDCl₃): 7.33-7.13 (m, 5H,Ar); 4.40 (s, 2H, CH ₂—Ar); 3.58 (t,2H, CH ₂—OH); 3.30-3.10 (m, 2H, Ar—CH₂—N—CH ₂); 2.51 (t, 4H, CH ₂—NH—CH₂); 1.70-1.20 [m, 19H, CH₂—(CH ₂)₄—CH₂, N—CH₂—CH ₂—CH₂ and t.Bu].

6-[4-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-butylamino]-hexan-1-ol(8g)

(R₃=H, q=1, y=4, m=5, R₁=BOC) from 7e and 1′a.

¹H-NMR (CDCl₃): 7.35-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar); 3.59 (t,2H, CH ₂—OH); 3.25-3.00 (m, 2H, N—CH₂); 2.58-2.50 (m, 4H, CH ₂—NH—CH ₂);1.60-1.20 [m, 21H, CH₂—(CH ₂)₂—CH₂, N—CH₂—(CH ₂)₄—CH₂ and t.Bu].

5-[3-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-propylamino]-pentan-1-ol(8h)

(R₃=H, q=1, y=3, m=4, R₁=BOC) from 7 f and 1′b.

¹H-NMR (CDCl₃): 7.33-7.10 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.59 (t,2H, CH ₂—OH); 3.30-3.10 (m, 2H, Ar—CH₂—N—CH ₂) 2.58-2.48 (m, 4H, CH₂—NH—CH ₂); 1.70-1.20 [m, 17H, CH₂—(CH ₂)₃—CH₂, N—CH₂—CH ₂—CH₂ andt.Bu].

3-[5-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-pentylamino]-propan-1-ol(8i)

(R₃=H, q=1, y=5, m=2, R₁=BOC) from 7d and 1′d.

¹H-NMR (CDCl₃): 7.33-7.13 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.80-3.73(m, 2H, CH₂—O); 3.23-3.05 (m, 2H, Ar—CH₂—N—CH ₂); 2.88-2.80 (m, 2H, N—CH₂—CH₂—CH₂—OH); 2.60-2.50 [m, 2H, (CH₂)₄—CH ₂—N]; 1.70-1.30 [m, 17H,CH₂—(CH ₂)₃—CH₂, CH₂—CH ₂—CH₂ and t.Bu].

EXAMPLE 7A

Preparation of the compounds of formula 9

Method A

To 1 equivalent of a compound of formula 8, prepared as described inexample 6A, dissolved in anhydrous CH₂Cl₂ 1.1 equivalents of BOC₂Odissolved in CH₂Cl₂ at 0° C. were added dropwise. After keeping understirring for 3 hours at room temperature, the solvent was evaporated,the residue was washed with water and extracted with CH₂Cl₂. Afterdrying and evaporation, an oily residue which was used without furtherpurification was obtained.

Method B

BOC₂O dissolved in a little dioxane was added dropwise to 1 equivalentof a compound of formula 8, prepared as described in example 6A,dissolved in a 2:1 dioxane:water mixture under stirring at 0° C.

The reaction mixture was brought to room temperature and after 2.5 hoursthe solution was concentrated by evaporating dioxane under reducedpressure.

After extraction with AcOEt, drying on Na₂SO₄ and filtration, thesolvent was evaporated under reduced pressure.

The crude was purified by flash chromatography on silica.

Method C

To 1 equivalent of a compound of formula 8 (R₁=H), prepared as describedin the patent application WO 96/18633, dissolved in CH₂Cl₂ 2.2equivalents of BOC₂O dissolved in CH₂Cl₂ at 0° C. were added dropwise.The mixture was kept under stirring for 3 hours at 0° C. and for further4 hours at room temperature. After evaporation of the solvent, theresidue was isolated and used without further purification.

The following compounds of formula 9 were obtained:

6-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexan-1-ol(9a)

(R₃=H, q=1, y=6, m=5, R₁=R₂=BOC) from 8a (method A).

Rf=0.54 (AcOEt:hexane=1:1)

6-[6-[N′-tert-Butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexan-1-ol(9b)

(R₃=2-CF₃, q=1, y=6, m=5, R₁=R₂=BOC) from 8b (method A).

6-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexan-1-ol(9c)

(R₃=H, q=1, y=5, m=5, R₁=R₂=BOC) from 8c (methods A and B).

Rf=0.40 (AcOEt:hexane=1:1)

¹H-NMR (CDCl₃): 1.16-1.58 (m, 32H, 7CH₂ and 2t.Bu); 3.10 (bs, 6H,3CH₂N); 3.61 (t, 2H, J=6.2 Hz, CH₂O); 4.40 (bs, 2H, CH₂Ph); 7.22-7.30(m, 5H, H arom.).

5-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentan-1-ol(9d)

(R₃=H, q=1, y=5, m=4, R₁=R₂=BOC) from 8d (methods A and B).

Rf=0.5 (AcOEt:hexane=1:1)

¹H-NMR (CDCl₃): 7.35-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.65-3.55(m, 2H, CH₂—O); 3.20-3.03 (m, 6H, Ar—CH₂—N—CH ₂ and CH ₂—N—CH ₂);1.65-1.10 [m, 30H, CH₂—(CH ₂)₃—CH₂, N—CH₂—(CH ₂)₃—CH₂ and t.Bu].

5-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-pentan-1-ol(9e)

(R₃=H, q=1, y=6, m=4, R₁=R₂=BOC) from 8e (method A).

Rf=0.45 (AcOEt:hexane=1:1)

6-[3(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-hexan-1-ol(9f)

(R₃=H, q=1, y=3, m=5, R₁=R₂=BOC) from 8f (method A).

¹H-NMR (CDCl₃): 7.35-7.13 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.60 (t,2H, CH ₂—OH); 3.25-3.00 (m, 6H, CH ₂—NCOO); 1.80-1.20 [m, 28H, CH₂—(CH₂)₄—CH₂, CH₂—CH₂—CH₂ and t.Bu].

6-[4-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexan-1-ol(9g)

(R₃=H, q=1, y=4, m=5, R₁=R₂=BOC) from 8g (method B).

¹H-NMR (CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar); 3.67-3.53(m, 2H, CH ₂ —OH); 3.25-3.00 (m, 6H, Ar—N—CH ₂ and CH ₂—N—CH ₂);1.60-1.15 [m, 30H, CH₂—(CH ₂)₂—CH₂, N—CH₂—(CH ₂)₄—CH₂ and t.Bu].

5-[3-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-pentan-1-ol(9h)

(R₃=H, q=1, y=3, m=4, R₁=R₂=BOC) from 8h (methods A and B).

¹H-NMR (CDCl₃): 7.35-7.13 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.61 (t,2H, CH ₂—OH); 3.25-3.00 (m, 6H, CH ₂—NCOO); 1.80-1.20 [m, 26H, CH₂—(CH₂)₃—CH₂, CH₂—CH ₂—CH₂ and t.Bu].

3-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-propan-1-ol(9i)

(R₃=H, q=1, y=5, m=2, R₁=R₂=BOC) from 8i (method B).

¹H-NMR (CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar); 3.60-3.49(m, 2H, CH₂—O); 3.35-3.00 (m, 6H, Ar—CH₂—N—CH ₂ and CH ₂—N—CH ₂); 2.90(bs, 1H, OH); 1.60-1.10 [m, 30H, CH₂—(CH ₂)₃—CH₂, N—CH₂—CH ₂—CH₂ andt.Bu].

2-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-ethanol(9k)

(R₃=H, q=1, y=6, m=1, R₁=R₂=BOC) from2-[6-(Phenylmethylamino)-hexylamino]-ethanol (method C).

2-[6-[N′-tert-Butoxycarbonyl-N′-(4-methoxyphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-ethanol(91)

(R₃=4-OCH₃, q=1, y=6, m=1, R₁=R₂=BOC) from2-[6-[(4-Methoxyphenyl)methyl-amino]-hexylamino]-ethanol (method C).

Rf=0.36 (AcOEt)

5-[4-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-pentan-1-ol(9m)

(R₃=H, q=1, y=4, m=4, R₁=R₂=BOC) from5-[4-(Phenylmethylamino)-butylamino]-pentan-1-ol (method C).

Rf=0.36 (AcOEt:hexane=1:1)

EXAMPLE 8A

Preparation of the compounds of formula 10 (II—r=1)

Method A

To 1 equivalent of a compound of formula 9, prepared as described inexample 7A, dissolved in DMF 3.5 equivalents of pyridinium dichromatewere added in 3 portions at room temperature. The dark mixture was keptunder stirring overnight. The reaction mixture was then evaporated undervacuum, AcOEt was added to the residue and the resultant solution wasfiltered. After drying on Na₂SO₄ and evaporation, the resultant residuewas purified by column or thin layer chromatography.

Method B

At 0° C. a solution containing 1 equivalent of a compound of formula 9,prepared as described in example 7A, a catalytic amount of TEMPO, acatalytic amount of Aliquate®, a catalytic amount of KBr, 1 portion of asaturated NAHCO₃ solution and 3 portions of CH₂Cl₂ was prepared. Asolution of NaClO (pH=8) was added to the solution at 0° C. Aliquots ofNaClO solution were added in 5 hours period up to the disappearance ofthe starting compound. After 5 hours at room temperature, a 1N NaOHsolution was added up to pH 12. The mixture was kept under stirring for2 hours and then the pH was brought to 4 by addition of a 1N HClsolution. The resultant mixture was extracted with AcOEt (3 times). Theorganic phases were dried on Na₂SO₄ and, after evaporation, an oil whichwas purified by column or thin layer chromatography was obtained.

The following compounds of formula 10 were obtained:

6-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexanoicacid (10a)

(R₃=H, q=1, y=6, m=5, R₁=R₂=BOC) from 9a (methods A and B).

Rf=0.33 (AcOEt:hexane=1:1)

¹H-NMR (CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.40 (s, 2H, CH ₂—Ar); 3.25-3.00(m, 6H, Ar—N—CH ₂ and CH ₂—N—CH ₂); 2.39-2.28 (m, 2H, CH ₂—COO);1.70-1.10 [m, 30H, CH₂—(CH ₂)₃—CH₂, N—CH₂—(CH ₂)₃—CH₂ and t.Bu].

6-[6-[N′-tert-Butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexanoicacid (10b)

(R₃=2-CF₃, q=1, y=6, m=5, R₁=R₂=BOC) from 9b (method A).

6-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoicacid (10c)

(R₃=H, q=1, y=5, m=5, R₁=R₂=BOC) from 9c (methods A and B).

Rf=0.4 (AcOEt:hexane=1:1)

¹H-NMR (CDCl₃): 1.14-1.68 (m, 30H, 6CH₂ and 2t.Bu); 2.20 (bs, 2H, CH₁C);3.05 (Bs, 6H, 3CH₂N); 4.35 (bs, 2H, CH₂Ph); 7.17-7.29 (m, 5H, H arom.).

5-[5-N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentanoicacid (10d)

(R₃=H, q=1, y=5, m=4, R₁=R₂=BOC) from 9d (method B).

Rf=0.36 (AcOEt:hexane=1:1)

¹H-NMR (200 Mhz, CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar);3.20-3.03 (m, 6H, Ar—CH₂—N—CH ₂ and CH ₂—N—CH ₂); 2.38-2.30 (m, 2H, CH₂—COO); 1.60-1.10 (m, 28H, CH₂—(CH ₂)₃—CH₂, N—CH₂—(CH ₂)₃—CH₂ and t.Bu).

5-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-pentanoicacid (10e)

(R₃=H, q=1, y=6, m=4, R₁=R₂=BOC) from 9e (method A).

Rf=0.18 (AcOEt:hexane=1:1)

6-[3(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-hexanoicacid (10f)

(R₃=H, q=1, y=3, m=5, R₁=R₂=BOC) from 9f (method B).

¹H-NMR (200 MHz, CDCl₃): 7.35-7.13 (m, 5H, Ar); 6.10 (bs, 1H, COOH);4.40 (s, 2H, CH ₂—Ar); 3.25-3.00 (m, 6H, 3CH ₂—NCOO); 2.31 (t, 2H, CH₂—COO): 1.80-1.20 (m, 26H, CH₂—(CH ₂)₃—CH₂, CH₂—CH ₂—CH₂ and t.Bu).

6-[4-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexanoicacid (10g)

(R₃=H, q=1, y=4, m=5, R₁=R₂=BOC) from 9g (method B).

¹H-NMR (200 MHz, CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar);3.25-3.00 (m, 6H, Ar—N—CH ₂ and CH ₂—N—CH ₂); 2.31 (t, 2H, CH ₂—COO);1.70-1.10 (m, 28H, CH₂—(CH ₂)₂—CH₂, N—CH₂—(CH ₂)₃—CH₂ and t.Bu).

5-[3N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-pentanoicacid (10h)

(R₃=H, q=1, y=3, m=4, R₁=R₂=BOC) from 9h (method B).

¹H-NMR (200 Mz, CDCl₃): 7.60 (bs, 1H, COOH); 7.35-7.13 (m, 5H, Ar); 4.40(s, 2H, CH ₂—Ar); 3.205-2,983.00 (m, 6H, 3H ₂—NCOO); 2.25-2.15 (m, 2H,CH ₂—COO); 1.80-1.20 (m, 24H, CH₂—(CH ₂)₂—CH₂, CH₂—CH ₂—CH₂ and t.Bu).

3-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-propanoicacid (10i)

(R₃=H, q=1, y=5, m=2, R₁=R₂=BOC) from 9i (method B).

¹H-NMR (200 MHz, CDCl₃): 7.33-7.15 (m, 5H, Ar); 4.39 (s, 2H, CH ₂—Ar);3.48-3.05 (m, 6H, Ar—CH₂—N—CH ₂ and CH ₂—N—CH ₂); 2.60-2.50 (m, 2H, CH₂—COO); 1.60-1.20 (m, 24H, CH₂—(CH ₂)₃—CH₂ and t.Bu).

[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-aceticacid (10k)

(R₃=H, q=1, y=6, m=1, R₁=R₂=BOC) from 9k (method A).

Rf=0.22 (AcOEt)

[6-[N′-tert-Butoxycarbonyl-N′-(4-methoxyphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-aceticacid (10)

(R₃=4-OCH₃, q=1, y=6, m=1, R₁=R₂=BOC) from 9l (method A).

Rf=0.29 (AcOEt:hexane=1:1)

5-[4-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-pentanoicacid (10m)

(R₃=H, q=1, y=4, m=4, R₁=R₂=BOC) from 9m (method A)

Rf=0.29 (AcOEt)

[6-(N′-Phenylmethoxycarbonyl-N′-phenylmethylamino)-N-phenylmethoxycarbonyl-hexylamino]-aceticacid (10n)

(R₃=H, q=1, y=6, m=1, R₁=R₂=BzOCO) from2-[6-(N′-Phenylmethoxycarbonyl-N′-phenylmethylamino)-N-phenylmethoxycarbonyl-hexylamino]-ethanol,described in WO 96/18633.

Rf=0.24 (AcOEt:CH₃OH=95:5) (method A)

EXAMPLE 9A

Preparation of the compounds of formula 5″ (II—r=0)

An excess (15 equivalents) of CF₃COOH was added to 1 equivalent of acompound of formula 5, prepared as described in example 3A, dissolved inCH₂Cl₂ at room temperature. After 6 hours under stirring, the solventwas evaporated under vacuum and the resultant residue (compound 5- R₁=H)was isolated and used without further purification.

To 1 equivalent of compound 5 (R₁=H) in CH₂Cl₂ 1.1 equivalents ofethylchloroformate and 5 equivalents of diisopropylethylamine were addedat 0° C. The reaction mixture was kept under stirring at roomtemperature overnight. After washing with water and with a saturatedNaHCO₃ solution, the organic phase was dried on Na₂SO₄ and evaporated.The resultant oily residue was purified by column or thin layerchromatography.

The following compound of formula 5″ was obtained:

6-(N-Ethoxycarbonyl-N-phenylmethylamino)-hexanoic acid (5″a)

(R₃=H, q=1, x=5, R_(1a)=EtOCO) from 5a.

Rf=0.16 (CH₂Cl₂:CH₃OH=9.5:0.5)

EXAMPLE 10A

Preparation of the compounds of formula 10″ (II—r=1)

Ethereal hydrochloric acid was added under stirring to 1 equivalent of acompound of formula 10, prepared as described in example 8A, dissolvedin a little Et₂O. After 5 hours the precipitate was filtered and washedwith Et₂O obtaining the corresponding compound of formula 10 (R₁=R₂=H).

An excess of acyl chloride and NaOH were contemporaneously addeddropwise to 1 equivalent of the compound of formula 10 (R₁=R₂=H) inCH₂Cl₂ and NaOH 1N under stirring at 0° C.

The organic phases were separated and the aqueous phase was extractedwith CH₂Cl₂.

The organic phase was dried on Na₂SO₄ and evaporated.

The following compounds of formula 10″ were obtained:

6-[5-(N′-Acetyl-N′-phenylmethylamino)-N-acetyl-pentylamino]-hexanoicacid (10″a)

(R₃=H, q=1, y=5, m=5, R_(1a)=R_(2a)=CH₃CO) from 10c.

¹H-NMR (200 MHz, CDCl₃): 7.40-7.10 (m, 5H, Ar), 4.59-4.50 (s, 2H, CH₂—Ar): 3.38-3.09 (m, 6H, 3CH₂—NCO); 2.38-2.27 (m, 2H, CH₂—COO);2.17-2.03 (5s, 6H, 2COCH₃); 1.72-1.12 [m, 12H, 2CH₂—(CH ₂)₃—CH₂).

6-[5-[N′-(2,2-Dimethylpropionyl)-N′-phenylmethylamino]-N-(2,2dimethylpropionyl)-pentylamino]-hexanoicacid (10″b)

[R₃=H, q=1, y=5, m=5, R_(1a)=R_(2a)=(CH₃)₃CCO] from 10c.

¹H-NMR (200 MHz, CDCl₃): 7.36-7.12 (m, 5H, Ar), 4.67 (s, 2H, CH ₂—Ar);3.30-3.15 (m, 6H, 3CH₂—NCOO); 2.33 (t, 2H, CH₂—COO); 1.70-1.10 [m, 30H,2CH₂—(CH ₂)₃—CH₂ and t.Bu].

Part B—Synthesis of the Compounds of Formula (I) EXAMPLE 1B

Preparation of the compounds of formula (I) wherein R₁ and R₂ aredifferent from hydrogen

Method A

To 1 equivalent of a compound of formula II, prepared as described inpart A, dissolved in CH₂Cl₂ or in anhydrous DMF (1-5 ml), 1 equivalentof(±)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinonefollowed by a solution of BOP (1.5 equivalents) and Et₃N (3 equivalents)was added. The reaction mixture was kept under stirring at roomtemperature for 3-5 hours. After evaporation to dryness, brine and AcOEtwere added. After extraction, the organic phase was dried on Na₂SO₄ andevaporated obtaining a mixture of compounds of formula I-A, I-B and I-Cwhich were separated by chromatography.

Method B

Under nitrogen atmosphere, 1 equivalent of CDI was added to 1 equivalentof a compound of formula II, prepared as described in part A, dissolvedin CHCl₃.

After 30 minutes 1 equivalent of(2S,5R)-4-(dimethylamino-methyleneamino)-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinoneor of the corresponding racemate was added under nitrogen atmosphere andthe reaction mixture was heated under-reflux.

After 24 hours the solvent was evaporated under reduced pressure and theresidue was taken with AcOEt.

After washing with water and separation of the phases, the organic phasewas evaporated under reduced pressure.

The residue was dissolved in a mixture CH₂Cl₂:CH₃OH=2:1 and aqueousacetic acid was added.

After one night, the solvent was evaporated under reduced pressure, theresidue was washed with a solution of NaHCO₃ and the resultant crude waspurified by flash-chromatography on silica (eluant CH₂Cl₂:CH₃OH=95:5).

The following compounds of formula (I) were obtained:

Compounds of formula I-A

(±)-4-Amino-1-[2-[6-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 1)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=BOC) from 10c (methods A and B).

Rf=0.4 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 1.72-1.55 (m, 32H, 7CH₂ and 2t.Bu); 2.35 (t, 2H, J=7.3Hz, CH₂CO); 3.02-3.10 (m, 6H, CH₂N); 3.46-3.55 (m, 2H, 2H-2′); 4.32-4.56(m, 4H, 2H-5′ and CH₂Ph); 5.31 (pseudo q, 1H, H-4′); 5.83 (bs, 1H, H-5);6.33 (pseudo t, 1H, H-1′); 7.17-7.34 (m, 5H, H arom.); 7.67 (d, 1H,J=5.8 Hz, H-6).

Mass (ionization TSP/DI⁺): 718 [M+H]⁺, 618 [718-BOC]⁺, 518 [618-BOC]⁺

(2S,5R)-4-Amino-1-[2-[6-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 2)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=BOC) from 10c (method B).

¹H-NMR (CDCl₃): 1.08-1.72 [m, 30H, 2CH₂—(CH ₂)₃—CH₂ and 2t.Bu]; 2.35 (t,2H, J_(HH)=7.30 Hz, CH₂—CO); 3.04-3.57 (m, 8H, CH₂—S and 3CH₂—N);4.32-4.58 (m, 4H, CH₂—Ph and COO—CH₂); 5.30-5.34 (m, 1H, CH—S);5.68-5.87 (bs, 1H, CH═CHN); 6.03-6.43 (bs, 2H, NH₂); 6.30-6.35 (m, 1H,N—CH—O); 7.16-7.33 (m, 5H, Ar); 7.73 (d, 1H, J_(HH)=7.4 Hz, ═CH—N—CO).

Mass (ionization TSP/DI⁺): 718 [M+H]⁺

(±)-4-Amino-1-[2-[6-[6-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 3)

(R₃=H, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10a (method A).

Rf=0.14 (AcOEt)

¹H-NMR (CDCl₃): 1.15-1.67 (m, 32H, 7CH₂ and 2t.Bu); 2.35-2.42 (m,2H,CH₂CO); 2.93-3.17 (m, 7H, 3CH₂N and H-2′a or H-2′b); 3.50-3.59 (m,1H, H-2′a or H-2′b); 3.83-4.10 (m, 2H, 2H-5′); 4.34 (bs, 2H, CH₂Ph);5.26 (pseudo d, 1H, H-4′); 6.26 (pseudo d, 1H, H-1′); 7.12-7.29 (m, 5H,H arom.); 7.35 (d, 1H, J=7.5 Hz, H-5); 8.37 (d, 1H, J=7.5 Hz, H-6).

(±)-4-Amino-1-[2-[6-(N-tert-butoxycarbonyl-N-phenylmethylamino)-hexanoyloxy-methyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 4)

(R₃=H, q=1, n=5, r=0, R₁=BOC) from 5a (methods A and B).

Rf=0.42 (AcOEt)

¹H-NMR (CDCl₃): 1.10-1.66 (m, 15H, 3CH₂ and t.Bu); 2.26 (t, 2H, J=7.5Hz, CH₂CO); 2.96-3.07 (m, 3H, CH₂N and H-2′a or H-2′b); 3.42-3.51 (m,1H, H-2′a or H-2′b); 4.26-4.32 (m, 3H, CH₂Ph and H-5′a or H-5′b);4.43-4.52 (m, 1H, H-5′a or H-5′b); 5.25 (q, 1H, J₁=3.2 Hz, J₂=5.0 Hz,H-4′); 5.72 (bs, 1H, H-5); 6.25 (pseudo t, 1H, H-1′); 7.10-7.40 (m, 5H,H arom.); 7.67 (d, 1H, J=7.3 Hz, H-6).

Mass (ionization TSP/DI⁺): 533 [M+H]⁺, 555 [M+Na]⁺, 252 [230+Na]⁺, 459

(2S,5R)-4-Amino-1-[2-[6-(N-tert-butoxycarbonyl-N-phenylmethylamino)-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 5)

(R₃=H, q=1, n=5, r=0, R₁=BOC) from 5a (method B).

¹H-NMR (DMSO); 7.68 (d, 1H, J_(HH)=7.5 Hz, CH═CH); 7.35-7.17 (m, 5H,Ar); 6.25-6.19 (m, 1H, N—CH—O); 5.75 (d, 1H, CH═CH); 5.36-5.32 (m, 1H,S—CH—O); 4.44-4.27 (m, 4H, CH₂—Ar and COOCH₂); 3.49-3.03 (m, 4H, CH₂—Sand CH₂—N); 2.31 (t, 2H, J_(HH)=7.20 Hz, CH₂—COO); 1.57-1.11 [m, 15H,CH₂—(CH ₂)₃—CH₂ and t.Bu].

Mass (ionization TSP/DI⁺): 533 [M+H]⁺

(±)-4-Amino-1-[2-[6-[N-tert-butoxycarbonyl-N-(3trifluoromethylphenyl)methyl-amino]-hexanoyloxymethyl-]1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 6)

(R₃=3-CF₃, q=1, n=5, r=0, R₁=BOC) from 5b (method A).

Rf=0.05 (AcOEt)

¹H-NMR (CDCl₃): 1.13-1.73 (m, 15H, 3CH₂ and t.Bu); 2.34 (t, 2H, J=7.4Hz, CH₂CO); 3.03-3.17 (m, 3H, CH₂N and H-2′a or H-2′b); 3.47-3.56 (m,1H, H-2′a or H-2′b); 4.32-4.56 (m, 4H, CH₂Ph and 2H-5′); 5.31 (pseudo q,1H, J₁=3.3 Hz, J₂=5.2 Hz, H-4′); 5.83 (t, 1H, J=7.5 Hz, H-5); 6.32 (t,1H, J=4.8 Hz, H-1′); 7.39-7.68 (m, 4H, H arom.); 7.72 (d, 1H, J=7.53 Hz,H-6).

(±)-4-Amino-1-[2-[6-[N-tert-butoxycarbonyl-N-(2-trifluoromethyl-phenyl)methyl-amino]-hexanoyloxymethyl-]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 7)

(R₃=2-CF₃, q=1, n=5, r=0, R₁=BOC) from 5c (method A).

Rf=0.05 (AcOEt)

¹H-NMR (CDCl₃): 1.18-1.68 (m, 15H, 3CH₂ and t.Bu); 2.35 (t, 2H, J=7.4Hz, CH₂CO); 3.05-3.23 (m, 3H, CH₂N and H-2′a or H-2′b); 3.49-3.73 (m,1H, H-2′a or H-2′b); 3.43-4.82 (m, 4H, CH₂Ph and 2H-5′); 5.30-5.35 (m,1H, H-4′); 6.33 (t, 1H, J=4.6 Hz, H-1′); 7.26-7.84 (m, 5H, H arom. andH-6).

(±)-4-Amino-1-[2-[6-[6-[N′-tert-butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 8)

(R₃=2-CF₃, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10b (method A).

Rf=0.05 (AcOEt)

¹H-NMR (CDCl₃): 1.10-1.74 (m, 32H, 7CH₂ and 2t.Bu); 2.37 (t, 2H, J=7.4Hz, CH₂CO); 3.10-3.23 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.51-3.64 (m,1H, H-2′a or H-2′b); 4.35-4.43 (m, 1H, H-5′a or H-5′b); 4.52-4.64 (m,3H, CH₂Ph and H-5′a or H-5′b); 5.34 (q, 1H, J₁=3.1 Hz, J₂=4.7 Hz, H-4′);5.85 (bs, 1H, H-5); 6.34 (pseudo t, 1H, H-1′); 7.26-7.64 (m, 5H, H arom.and H-5); 7.78 (d, 1H, J=7.2 Hz, H-6).

(±)-4-Amino-1-[2-[6-(N-ethoxycarbonyl-N-phenylmethylamino)-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 9)

(R₃=H, q=1, n=5, r=0, R₁=EtOCO) from 5″a (method A).

Rf=0.05 (AcOEt)

¹H-NMR (CDCl₃): 1.10-1.60 (m, 9H, 3CH₂ and CH₃); 2.25 (t, 2H, J=7.5 Hz,CH₂CO); 2.90-3.20 (m, 3H, CH₂N and H-2′a or H-2′b); 3.40-3.50 (m, 1H,H-2′a or H-2′b); 4.00-4.20 (m, 2H, CH ₂CH₃); 4.25-4.50 (m, 4H, CH₂Ph and2H-5′); 5.20-5.25 (m, 1H, H-4′); 5.70-5.85 (m, 1H, H-5); 6.20-6.30 (m,1H, H-1′); 7.05-7.25 (m, 5H, H arom.); 7.50-7.65 (m, 1H, H-6).

(±)-4-Amino-1-[2-[(N-tert-butoxycarbonyl-N-phenylmethylamino)-acetyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 10)

(R₃=H, q=1, n=1, r=0, R₁=BOC) from 5g (method A).

Rf=0.05 (AcOEt)

¹H-NMR (CDCl₃): 1.40 (m, 9H, t.Bu); 2.90-3.00 (m, 1H, H-2′a or H-2′b);3.35-3.45 (m, 1H, H-2′a or H-2′b); 3.75-3.90 (m, 2H, CH₂N); 4.20-4.55(m, 5H, CH₂Ph and 2H-5′); 5.15-5.25 (m, 1H, H-4′); 5.70-5.80 (m, 1H,H-5); 6.20-6.30 (q, 1H, J₁=5.0 Hz, J₂=10.0 Hz, H-1′); 7.10-7.30 (m, 5H,H arom.); 7.45-7.55 (m, 1H, H-6).

(±)-4-amino-1-[2-[4-(N-tert-butoxycarbonyl-N-phenylmethylamino)-butanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 11)

(R₃=H, q=1, n=3, r=0, R₁=BOC) from 5e (method B).

¹H-NMR (CDCl₃): 7.72 (d, 1H, J_(HH)=7.5 Hz, CH═CH); 7.34-7.15 (m, 5H,Ar); 6.33-6.28 (m, 1H, N—CH—O); 5.80 (bs, 1H, CH═CH); 5.33-5.38 (m, 1H,S—CH—O); 4.56-4.32 (m, 4H, CH₂—Ar and COOCH₂); part AB of an ABX system;VA=3.51, VB=3.08, JAB=12.2 Hz, JAX=5.3 Hz, JBX=4.0 Hz, CH₂S; 3.28-3.14(m, 2H, CH₂—CH₂—N); 2.34 (t, 2H, J_(HH)=7.5 Hz, CH₂COO); 1.90-1.75 (m,2H, CH₂—CH ₂—CH₂); 1.43 (s, 9H, t.Bu).

Mass (ionization TSP/DI⁺); 550 [M+H]⁺, 527 [M+Na]⁺

(±)-4-Amino-1-[2-[6-[4-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 12)

(R₃=H, q=1, n=4, r=1, m=5, R₁=R₂=BOC) from 10g (method B).

¹H-NMR (CDCl₃): 7.77 (d, 1H, J_(HH)=7.5 Hz, CH═CH); 7.33-7.17 (m, 5H,Ar); 6.37 (bs, 2H, NH₂); 6.34-6.29 (m, 1H, N—CH—O); 5.85 (bs, 1H,CH═CH); 5.34-5.30 (m, 1H, S—CH—O); 4.60-4.33 (m, 4H, CH₂—Ar and COOCH₂);3.58-3.06 (m, 6H, Ar—CH₂—N—CH ₂ and CH ₂—N—CH ₂); 2.35 (t, 2H,J_(HH)=7.4 Hz, CH₂COO); 1.71-1.21 [m, 28H, CH₂—(CH ₂)₃—CH₂—N and 2t.Bu).

Mass (ionization TSP/DI⁺): 704 [M+H]⁺, 726 [M+Na]⁺, 459

(±)-4-Amino-1-[2-[6-[3-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 13)

(R₃=H, q=1, n=3, r=1, m=5, R₁=R₂=BOC) from 10f (method B).

¹H-NMR (DMSO): 7.68 (d, 1H, CH═CH); 7.39-7.17 (m, 5H, Ar); 6.25-6.19 (m,1H, N—CH—O); 5.73 (d, 1H, CH═CH); 5.36-5.32 (m, 1H, S—CH—O); 4.45-4.27(m, 4H, CH₂—Ar and COOCH₂); 3.48-2.98 (m, 8H, CH₂—S and 3CH₂—NCOO); 2.34(t, 2H, CH₂COO); 1.65-1.13 [m, 26H, CH₂—(CH ₂)₃—CH₂, CH₂—CH ₂—CH₂ andt.Bu].

Mass (ionization TSP/DI⁺): 690 [M+H]⁺, 712 [M+Na]⁺, 252 [230+Na]⁺

(±)-4-Amino-1-[2-[5-[3(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 14)

(R₃=H, q=1, n=3, r=1, m=4, R₁=R₂=BOC) from 10h (method 13).

¹H-NMR (CDCl₃): 7.92-7.70 (bs, 1H, CH═CH); 7.35-7.15 (m, 5H, Ar);6.33-6.29 (m, 1H, N—CH—O); 6.42 (bsd, 2H, NH₂); 5.98-5.80 (bs, 1H,CH═CH); 5.35-5.30 (m, 1H, CH—S); 4.64-4.35 (m, 4H, CH₂—Ar and CH₂O);3.60-3.00 (m, 8H, CH₂—S and 3CH₂—NCOO); 2.42-2.33 (m, 2H, CH₂COO);1.70-1.33 [m, 24H, CH₂—(CH ₂)₂—CH₂, CH₂—CH ₂—CH₂ and t.Bu].

Mass (ionization TSP/DI⁺): 676 [M+H]⁺, 576 [676-BOC]⁺, 459

(2S,5R)-4-Amino-1-[2-[5-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 15)

(R₃=H, q=1, n=5, r=1, m=4, R₁=R₂=BOC) from 10d (method B).

¹H-NMR (CDCl₃): 7.82-7.60 (bs, 1H, CH═CH); 7.35-7.12 (m, 5H, Ar);6.33-6.29 (m, 1H, N—CH—O); 5.95-5.75 (bd, 1H, CH═CH); 5.35-5.28 (m, 1H,CH—S); 4.60-4.30 (m, 4H, CH₂—Ar and CH₂O); 3.55-3.00 (m, 8H, CH₂—S and3CH₂—NCOO); 2.41-2.30 (m, 2H, CH₂COO); 1.70-1.10 [m, 28H, CH₂—(CH₂)₃—CH₂, CH₂—(CH ₂)₂—CH₂ and t.Bu].

Mass (ionization TSP/DI⁺): 704 [M+H]⁺, 726 [M+Na]⁺

(±)-4-Amino-1-[2-[3-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 16)

(R₃=H, q=1, n=5, r=1, m=2, R₁=R₂=BOC) from 10i (method B).

¹H-NMR (CDCl₃): 7.71 (bs, 1H, CH═CH); 7.35-7.12 (m, 5H, Ar); 6.33-6.29(m, 1H, N—CH—O); 5.88-5.80 (bd, 1H, CH═CH); 5.35-5.30 (m, 1H, CH—S);4.60-4.30 (m, 4H, CH₂—Ar and CH₂O); 3.60-3.00 (m, 8H, CH₂—S and3CH₂—NCOO); 2.65-2.54 (m, 2H, CH₂COO); 1.60-1.10 [m, 24H, CH₂—(CH₂)₃—CH₂ and t.Bu].

Mass (ionization TSP/DI⁺): 676 [M+H]⁺, 698 [M+C₃H₇]⁺, 459, 252 [230+Na]⁺

(±)-4-Amino-1-[2-[5-(N-tert-butoxycarbonyl-N-phenylmethylamino)-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 17)

(R₃=H, q=1, n=4, r=0, R₁=BOC) from 5d (method B).

¹H-NMR (CDCl₃): 7.89-7.65 (bs, 1H, CH═CH); 7.35-7.15 (m, 5H, Ar);6.35-6.30 (m, 1H, N—CH—O); 5.95-5.70 (bs, 1H, CH═CH); 5.33-5.29 (m, 1H,CHS); 4.60-4.33 (m, 4H, CH₂—Ar and OCH₂); 3.58-3.02 (m, 4H, CH₂S and CH₂—NCOO); 2.41-2.30 (m, 2H, CH₂COO); 1.70-1.35 [m, 13H, CH₂—(CH ₂)₂—CH₂and t.Bu].

Mass (ionization TSP/DI⁺): 519 [M+H]⁺

(±)-4-Amino-1-[2-[6-[5-(N′-acetyl-N′-phenylmethylamino)-N-acetyl-pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 18)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=Ac) from 10″a (method B).

¹H-NMR (DMSO): 7.69 (d, 1H, CH═CH); 7.40-7.15 (m, 5H, Ar); 6.25-6.18 (m,1H, N—CH—O); 5.78-5.72 (m, 1H, CH═CH); 5.39-5.31 (m, 1H, S—CH—O);4.55-4.26 (m, 4H, CH₂—Ar and COOCH₂); 3.48-3.05 (m, 8H, CH₂—S and3CH₂—NCOO); 2.40-2.27 (m, 2H, CH₂COO); 2.10-1.90 (3s, 6H, 2COCH₃);1.60-1.05 [m, 12H, CH₂—(CH₂)₃—CH₂ and CH₂—(CH₂)₃—CH₂].

Mass (ionization TSP/DI⁺): 602 [M+H]⁺, 624 [M+Na]⁺, 459

(±)-4-Amino-1-[2-[6-[5-[N′-(2,2-Dimethylpropionyl))-N′-phenylmethylamino]-N-(2,2-dimethylpropionyl)-pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 19)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=Piv) from 10″b (method B).

¹H-NMR (CDCl₃): 7.81 (d,═CH—N—CO); 7.38-7.12 (m, 5H, Ar); 6.37-6.30 (m,1H, N—CH—O); 5.91 (m, 1H, CH═CHN); 5.36-5.31 (m, 1H, CHS); 4.69-4.61 (s,2H, CH₂—Ar) 4.61-4.35 (m, 2H, COOCH₂); 3.60-3.10 (m, 8H, CH₂—S and3CH₂—N); 2.38 (t, 2H, CH₂CO); 1.75-1.10 [m, 30H, 2CH₂—(CH ₂)₃—CH₂ and2t.Bu].

Mass (ionization TSP/DI⁺): 686 [M+H]⁺, 708 [M+Na]⁺, 1372 [2M+H]⁺

(±)-4-Amino-1-[2-[5-[6-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 20)

(R₃=H, q=1, n=6, r=1, m=4, R₁=R₂=BOC) from 10e (method A). which wasdirectly used in the subsequent reaction.

Compounds of formula I-B

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[[6-(N′-phenylmethoxycarbonyl-N′-phenylmethylamino)-N-phenylmethoxycarbonyl-hexylamino]-acetylamino]-2(1H)-pyrimidinone(Compound 21)

(R₃=H, q=1, n=6, r=1, m=1, R₁=R₂=BzOCO) from 10n (method A)

¹H-NMR (CDCl₃): 1.00-1.45 (m, 8H, 4CH₂); 2.95-3.30 (m, 5H, 2CH₂N andH-2′a or H-2′b); 3.40-3.45 (m, 1H, H-2′a or H-2′b); 3.75-4.10 (m, 4H,CH₂CO and 2H-5′); 4.35 (bs, 2H, CH₂Ph); 5.05 (bs, 4H, 2CH₂O); 5.20(pseudo t, 1H, H-4′); 6.20 (pseudo q, 1H, H-1′); 7.00-7.30 (m, 16H, Harom. and H-5); 8.30 (d, 1H, J=7.5 Hz, H-6), 9.35 (bs, 1H, NHCO).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[[6-[N′-tert-butoxycarbonyl-N′-(4-methoxyphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-acetylamino]-2(1H)-pyrimidinone(Compound 22)

(R₃=4-OCH₃, q=1, n=6, r=1, m=1, R₁=R₂=BOC) from 10l (method A)

Rf=0.2 (AcOEt)

¹H-NMR (CD₃OD): 1.30-1.60 (m, 26H, 4CH₂ and 2t.Bu); 3.05-3.35 (m, 5H,2CH₂N and H-2′a or H-2′b); 3.60-3.70 (m, 1H, H-2′a or H-2′b); 3.80 (s,3H, CH₃); 3.95-4.30 (m, 4H, CH₂CO and 2H-5′); 4.35 (bs, 2H, CH₂Ph); 5.35(pseudo t, 1H, H-4′); 6.35 (pseudo q, 1H, H-1′); 6.80-7.30 (m, 4H, Harom.); 7.40 (d, 1H, J=7.5 Hz, H-5); 8.45 (d, 1H, J=7.5 Hz, H-6); 9.05(bs, 1H, NHCO).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 23)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=BOC) from 10c (method A)

Rf=0.36 (CH₂Cl₂:CH₃OH=9:1)

¹H-NMR (CDCl₃): 1.10-1.76 (m, 30H, 6CH₂ and 2t.Bu), 2.44 (t, 2H, J=7.3Hz, CH₂CO); 3.11-3.25 (m, 7H, CH₂N and H-2′a or H-2′b); 3.57-3.66 (m,1H, H-2′a or H-2′b); 3.91-4.17 (m, 2H, 2H-5′); 4.40 (bs, 2H, CH₂Ph);5.33 (pseudo t, 1H, H-4′); 6.32 (pseudo q, 1H, H-1′); 7.18-7.35 (m, 5H,H arom.); 7.41 (d, 1H, J=7.5 Hz, H-5); 8.41 (d, 1H, J=7.5 Hz, H-6); 8.98(bs, 1H, NHCO).

(±)-1(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-4-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 24)

(R₃=H, q=1, n=4, r=1, m=5, R₁=R₂=BOC) from 10g (method A)

¹H-NMR (CDCl₃): 1.15-1.75 (m, 28H, 5CH₂ and 2t.Bu); 2.35-2.60 (t, 2H,J=7.0 Hz, CH₂CO); 3.00-3.25 (m, 13H, 6CH₂N and H-2′a or H-2′b);3.50-3.65 (m, 1H, H-2′a or H-2′b); 3.85-4.20 (m, 2H, 2H-5′); 4.40 (bs,2H, CH₂Ph); 5.30 (pseudo t, 1H, H-4′); 6.30 (pseudo t, 1H, H-1′),7.15-7.35 (m, 5H, H arom.); 7.45 (d, 1H, J=7.5 Hz, H-5); 8.45 (d, 1H,J=7.5 Hz, H-6); 9.45 (bs, 1H, NHCO).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[6-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 25)

(R₃=H, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10a (method A)

Rf=0.23 (AcOEt)

¹H-NMR (CDCl₃): 1.05-1.86 (m, 32H, 7CH₂— and 2t.Bu); 2.11-2.41 (m, 4H,CH₂CO); 2.87-3.16 (m, 7H, 3CH₂N and H-2′a or H-2′b); 3.53-3.62 (m, 1H,H-2′a or H-2′b); 4.34-4.41 (m, 3H, CH₂Ph and H-5′a or H-5′b); 4.52-4.61(m, 1H, H-5′a or H-5′b); 5.32 (pseudo d, 1H, H-4′); 6.25 (pseudo d, 1H,H-1′); 7.12-7.29 (m, 5H, H arom.); 7-40 (d, 1H, J=7.5 Hz, H-5); 8.10 (d,1H, J=7.5 Hz, H-6), 9.00 (bs, 1H, NHCO).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[6[-N′-tert-butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 26)

(R₃=2-CF₃, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10b (method A)

Rf=0.4 (AcOEt)

¹H-NMR (CDCl₃): 1.17-1.69 (m, 32H, 7CH₂— and 2t.Bu); 2.45 (t, 2H, J=7.1Hz, CH₂CO); 3.10-3.23 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.55-3.64 (m,1H, H-2′a or H-2′b); 3.90-4.15 (m, 2H, 2H-5′); 4.57-4.62 (m, 2H, CH₂Ph);5.33 (t, 1H, J=2.9 Hz H-4′); 6.30 (q, 1H, J₁=3.3 Hz, J₂=5.0 Hz, H-1′);7.26-7.63 (m, 5H, H arom. and H-5); 8.42 (d, 1H, J=7.5 Hz, H-6); 9.27(bs, 1H, NHCO).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-(N-tert-butoxycarbonyl-N-phenylmethylamino)-hexanoylamino]-2(1H)-pyrimidinone (Compound 27)

(R₃=H, q=1, n=5, r=0, R₁=BOC) from 5a (method A)

Rf=0.52 (AcOEt)

¹H-NMR (CDCl₃): 1.12-1.67 (m, 15H, 3CH₂— and t.Bu); 2.34 (t, 2H, J=7.5Hz, CH₂CO); 3.06-3.13 (m, 3H, CH₂N and H-2′a or H-2′b); 3.54—3.54 (m,1H, H-2′a or H-2′b); 3.80-4.06 (m, 2H, 2H-5′); 4.30 (bs, 2H, CH₂Ph);5.22 (t, 1H, J=3.0 Hz, H-4′); 6.22 (pseudo q, 1H, J₁=3.2 Hz, J₂=5.1 Hz,H-1′); 7.08-7.25 (m, 5H, H arom.); 7.33 (d, 1H, J=7.5 Hz, H-5); 8.33 (d,1H, J=7.5 Hz, H-6); 9.62 (bs, 1H, NHCO).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[N-tert-butoxycarbonyl-N-(3-trifluoromethylphenyl)methylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 28)

(R₃=3-CF₃, q=1, n=5, r=0, R₁=BOC) from 5b (method A)

Rf=0.23 (AcOEt)

¹H-NMR (CDCl₃): 1.12-1.69 (m, 15H, 3CH₂— and t.Bu); 2.43 (m, 2H, J=7.3Hz, CH₂CO); 3.15-3.23 (m, 3H, CH₂N and H-2′a or H-2′b); 3.54-3.63 (m,1H, H-2′a or H-2′b); 3.81-4.15 (m, 2H, 2H-5′); 4.41 (bs, 2H, CH₂Ph);5.31 (t, 1H, J=2.8 Hz, H-4′); 6.30 (pseudo q, 1H, J₁=3.1 Hz, J₂=5.0 Hz,H-1′); 7.38-7.68 (m, 5H, H arom. and H-5); 8.40 (d, 1H, J=7.5 Hz, H-6);9.37 (bs, 1H, NHCO).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[N-tert-butoxycarbonyl-N-(2-trifluoromethylphenyl)methylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 29)

(R₃=2-CF₃, q=1, n=5, r=0, R₁=BOC) from 5c (method A)

Rf=0.4 (AcOEt)

¹H-NMR (CDCl₃): 1.18-1.68 (m, 15H, 3CH₂— and t.Bu); 2.43 (t, 2H, J=7.3Hz, CH₂CO); 3.16-3.24 (m, 3H, CH₂N and H-2′a or H-2′b); 3.56-3.64 (m,1H, H-2′a or H-2′b); 3.90-4.16 (m, 2H, 2H-5′); 4.58-4.63 (m, 2H, CH₂Ph);5.33 (t, 1H, J=3.0 Hz, H-4′); 6.30 (q, 1H, J₁=3.4 Hz, J₂=5.0 Hz, H-1′);7.26-7.63 (m, 5H, H arom. and H-5); 8.39 (d, 1H, J=7.5 Hz, H-6); 9.24(bs, 1H, NHCO).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-(N-ethoxycarbonyl-N-phenylmethylamino)-hexanoylamino]-2(1H)-pyrimidinone(Compound 30)

(R₃=H, q=1, n=5, r=0, R₁=EtOCO) from 5″a (method A)

Rf=0.2 (AcOEt)

¹H-NMR (CDCl₃): 1.10-1.70 (m, 9H, 3CH₂— and CH₃); 2.05-2.45 (m, 3H,2CH₂CO and OH); 3.00-3.20 (m, 3H, CH₂N and H-2′a or H-2′b); 3.45-3.60(m, 1H, H-2′a or H-2′b); 3.80-3.90 (m, 1H, H-5′a or H′-5b); 3.95-4.20(m, 3H, CH ₂CH₃ and H-5′a or H-5′b); 4.30-4.45 (bs, 2H, CH₂Ph);5.25-5.30 (m, 1H, H-4′); 6.20-6.30 (m, 1H, H-1′); 7.05-7.30 (m, 5H, Harom.); 7.35 (d, 1H, J=7.5 Hz, H-5); 8.30 (d, 1H, J=7.5 Hz, H-6), 9.40(bs, 1H, NH).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[(N-tert-butoxycarbonyl-N-phenylmethylamino)-acetylamino]-2(1H)-pyrimidinone(Compound 31)

(R₃=H, q=1, n=1, r=0, R₁=BOC) from 5g (method A)

Rf=0.35 (AcOEt)

¹H-NMR (CDCl₃): 1.40 (m, 9H, t.Bu); 3.10-3.20 (m, 1H, H-2′a or H-2′b);3.45-3.55 (m, 1H, H-2′a or H-2′b); 3.80-4.10 (m, 4H, CH₂N and 2H′-5);4.45 (bs, 2H, CH₂Ph); 5.20-5.25 (m, 1H, H-4′); 6.10-6.15 (m, 1H, H-1′);7.10-7.30 (m, 6H, H arom. and H-5); 8.30 (d, 1H, J=7.4 Hz, H-6).

(±)-1-(2Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[5-[6-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-pentanoylamino]-2(1H)-pyrimidinone(Compound 32)

(R₃=H, q=1, n=6, r=1, m=4, R₁=R₂=BOC) from 10e (method A) which wasdirectly used in the subsequent reaction.

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[3-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 33)

(R₃=H, q=1, n=3, r=1, m=5, R₁=R₂=BOC) from 10f (method A) which wasdirectly used in the subsequent reaction.

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[5-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentanoylamino]-2(1H)-pyrimidinone(Compound 34)

(R₃=H, q=1, n=5, r=1, m=4, R₁=R₂=BOC) from 10d (method A) which wasdirectly used in the subsequent reaction.

Compounds of formula I-C

(±)-4-[[6-(N′-Phenylmethoxycarbonyl-N′-phenylmethylamino)-N-phenylmethoxycarbonyl-hexylamino]-acetylamino]-1-[2-[[6-(N′-phenylmethoxycarbonyl-N′-phenylmethylamino)-N-phenylmethoxycarbonyl-hexylamino]-acetoxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 35)

(R₃=H, q=1, n=6, r=1, m=1, R₁=R₂=BzOCO) from 10n (method A)

¹H-NMR (CDCl₃): 1.10-1.45 (m, 16H, 8CH₂); 3.00-3.30 (m, 9H, 4CH₂N andH-2′a or H-2′b); 3.40-3.55 (m, 1H, H-2′a or H-2′b); 3.85-4.05 (m, 5H,2CH₂CO and H-5′a or H-5′b); 4.30-4.50 (m, 5H, 2CH₂Ph and H-5′a orH-5′b); 5.00 (bs, 8H, 4CH₂O); 5.20 (pseudo t, 1H, H-4′); 6.15 (pseudo q,1H, H-1′); 7.00-7.30 (m, 3H, H arom. and H-5); 7.95 (d, 1H, J=7.5 Hz,H-6); 9.00 (bs, 1H, NHCO).

(±)-4-[6-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexanoylamino]-1-[2-[6-[6-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 36)

(R₃=H, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10a (method A)

¹H-NMR (CDCl₃): 1.06-1.80 (m, 64H, 14CH₂ and 4t.Bu); 2.28-2.41 (m, 4H,2CH₂CO); 2.95-3.17 (m, 13H, 6CH₂N and H-2′a or H-2′b); 3.52-3.61 (m, 1H,H-2′a or H-2′b); 4.34-4.41 (m, 5H, 2CH₂Ph and H-5′a or H-5′b); 4.52-4.61(m, 1H, H-5′a or H-5′b); 5.32 (pseudo d, 1H, H-4′); 6.25 (pseudo d, 1H,H-1′); 7.13-7.34 (m, 10H, H arom.); 7.38 (d, 1H, J=7.5 Hz, H-5); 8.04(d, 1H, J=7.5 Hz, H-6); 8.90 (bs, 1H, NHCO).

(±)-4-[6-[5-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoylamino]-1-[-6-[5-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 37)

(R₃=H, q=1, n=5, r=1, m=5, R₁=R₂=BOC) from 10c (method A)

Rf=0.75 (AcOEt)

¹H-NMR (CDCl₃): 1.09-1.77 (m, 60H, 12CH₂ and 4t.Bu); 2.40 (q, 4H, J₁=7.0Hz, J₂=13.0 Hz, CH₂CO); 2.99-3.24 (m, 13H, 6CH₂N and H-2′a or H-2′b);3.58-3.67 (m, 1H, H-2′a or H-2′b); 4.40-4.46 (m, 5H, 2CH₂Ph and H-5′a orH-5′b); 4.58-4.67 (m, 1H, H-5′a or H-5′b); 5.38 (pseudo t, 1H, H-4′),6.31 (pseudo q, 1H, H-1′); 7.23-7.36 (m, 10H, H arom.); 7.43 (d. 1H,J=7.5 Hz, H-5); 8.10 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[6-[4-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexanoylamino]-1-[2-[6-[4-(N′-tert-butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-butylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 38)

(R₃=H, q=1, n=4, r=1, m=5, R₁=R₂=BOC) from 10g (method A)

¹H-NMR (CDCl₃): 1.15-1.80 (m, 56H, 10CH₂ and 4t.Bu); 2.25-2.50 (m, 4H,2CH₂CO); 3.00-3.30 (m, 13H, 6CH₂N and H-2′a or H-2′b); 3.60-3.70 (m, 1H,H-2′a or H-2′b); 4.35-4.50 (bs, 5H, 2CH₂Ph and H-5′a or H-5′b);4.60-4.70 (m, 1H, H-5′a or H-5′b); 5.35 (pseudo t, 1H, H-4′); 6.30(pseudo t, 1H, H-1′); 7.15-7.40 (m, 10H, H arom.); 7.50 (d, 1H, J=7.5Hz, H-5); 8.15 (d, 1H, J=7.5 Hz, H-6); 10.25 (bs, 1H, NHCO).

(±)-4-[6-(N-tert-Butoxycarbonyl-N-phenylmethylamino)-hexanoylamino]-1-[2-[6-(N-tert-butoxycarbonyl-N-phenylmethylamino)-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 39)

(R₃=H, q=1, n=5, r=0, R₁=BOC) from 5a (method A)

Rf=0.7 (AcOEt)

¹H-NMR (CDCl₃): 1.16-1.68 (m, 30H, 6CH₂ and 2t.Bu); 2.18-2.38 (m, 4H,2CH₂CO); 2.88-3.12 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.49-3.58 (m, 1H,H-2′a or H-2′b); 4.34 (bs, 5H, 2CH₂Ph and H-5′a or H-5′b); 4.49-4.57 (m,1H, H-5′a or H-5′b); 5.28 (pseudo q, 1H, J₁=3.1 Hz, J₂=4.8 Hz, H-4′);6.22 (pseudo q, 1H, J₁=3.0 Hz, J₂=5.1 Hz, H-1′); 7.10-7.26 (m, 10H, Harom.); 7.37 (d, 1H, J=7.5 Hz, H-5); 8.03 (d, 1H, J=7.5 Hz, H-6); 9.39(bs, 1H, NHCO).

(±)-4-[6-[N-tert-Butoxycarbonyl-N-(3-trifluoromethylphenyl)methylamino]-hexanoyl-amino]-1-[2-[6-[N-tert-butoxycarbonyl-N-(3-trifluoromethylphenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 40)

(R₃=3-CF₃, q=1, n=5, r=0, R₁=BOC) from 5b (method A)

Rf=0.5 (AcOEt)

¹H-NMR (CDCl₃): 1.14-1.76 (m, 30H, 6CH₂ and 2t.Bu); 2.32-2.45 (m, 4H,2CH₂CO); 3.16-3.24 (m, 5H, CH₂N and H-2′a or H-2′b); 3.57-3.60 (m, 1H,H-2′a or H-2′b); 4.44-4.67 (m, 6H, 2CH₂Ph and 2H-5′); 5.37 (pseudo q,1H, H-4′); 6.29 (pseudo q, 1H, H-1′); 7.40-7.70 (m, 11H, H arom. andH-5); 8.12 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[6-[N-tert-Butoxycarbonyl-N-(2-trifluoromethylphenyl)methylamino]-hexanoyl-amino]-1-[2-[6-[N-tert-butoxycarbonyl-N-(2-trifluoromethylphenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 41)

(R₃=2-CF₃, q=1, n=5, r=0, R₁=BOC) from 5c (method A)

Rf=0.6 (AcOEt)

¹H-NMR (CDCl₃): 1.16-1.65 (m, 30H, 6CH₂ and 2t.Bu); 2.30-2.46 (m, 4H,2CH₂CO); 3.03-3.24 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.58-3.67 (m, 1H,H-2′a or H-2′b); 4.37-4.45 (m, 1H, H-5′a or H-5′b); 4.58-4.64 (m, 5H,2CH₂Ph and H-5′a or H-5′b); 5.38 (q, 1H, J₁=3.2 Hz, J₂=4.9 Hz, H-4′);6.32 (q, 1H, J₁=3.0 Hz, J₂=5.4 Hz, H-1′); 7.26-7.64 (m, 9H, H arom. andH-5); 8.12 (d, 1H, J=7.5 Hz, H-6); 8.85 (bs, 1H, NHCO).

(±)-4-[6-[6[-N′-tert-Butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexanoylamino]-1-[2-[6-[6-[N′-tert-butoxycarbonyl-N′-(2-trifluoromethylphenyl)methylamino]-N-tert-butoxycarbonyl-hexylamino]-hexanoyloxymethyl]-13-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 42)

(R₃=2-CF₃, q=1, n=6, r=1, m=5, R₁=R₂=BOC) from 10b (method A)

¹H-NMR (CDCl₃): 1.12-1.73 (m, 64H, 14CH₂ and 4t.Bu); 2.34-2.49 (m, 4H,2CH₂CO); 3.02-3.22 (m, 9H, 4CH₂N and H-2′a or H-2′b); 3.58-3.67 (m, 1H,H-2′a or H-2′b); 4.37-4.45 (m, 1H, H-5′a or H-5′b); 4.57-4.63 (m, 9H,4CH₂Ph and H-5′a or H-5′b); 5.38 (q, 1H, J₁=3.2 Hz, J₂=5.0 Hz, H-4′);6.31 (q, 1H, J₁=3.2 Hz, J₂=5.0 Hz, H-1′); 7.26-7.63 (m, 9H, H arom. andH-5); 8.10 (d, 1H, J=7.5 Hz, H-6); 8.90 (bs, 1H, NHCO).

(±)-4-[6-(N-Ethoxycarbonyl-N-phenylmethylamino)-hexanoylamino]-1-[2-[6-(N-ethoxycarbonyl-N-phenylmethylamino)-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 43)

(R₃=H, q=1, n=5, r=0, R₁=EtOCO) from 5″a (method A)

¹H-NMR (CDCl₃): 1.10-1.70 (m, 18H, 6CH₂ and 2CH₃); 2.20-2.40 (m, 4H,2CH₂CO); 3.00-3.20 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.50-3.60 (m, 1H,H-2′a or H-2′b); 4.05 (q, 4H, J₁=6.9 Hz, J₂=13.9 Hz, 2CH ₂CH₃);4.30-4.45 (m, 5H, 2CH₂Ph and H-5′a or H-5′b); 4.50-4.60 (m, 1H, H-5′a orH-5′b); 5.25-5.35 (m, 1H, H-4′); 6.20-6.31 (m, 1H, H-1′); 7.05-7.25 (m,10H, H arom.); 7.35 (d, 1H, J=7.5 Hz, H-5); 8.05 (d, 1H, J=7.5 Hz, H-6);8.75 (bs, 1H, NH).

(±)-4-[(N-Ethoxycarbonyl-N-phenylmethylamino)-acetylamino]-1-[2-[(N-ethoxycarbonyl-N-phenylmethylamino)-acetyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 44)

(R₃=H, q=1, n=1, r=0, R₁=BOC) from 5g (method A)

¹H-NMR (CDCl₃): 1.40 (m, 18H, 2t.Bu); 3.05-3.15 (m, 1H, H-2′a or H-2′b);3.45-3.55 (m, 1H-2′a or H-2′b); 3.75-4.00 (m, 5H, 2CH₂N and H-5′a orH-5′b); 4.25-4.50 (m, 5H, 2CH₂Ph and H-5′a or H-5′b); 5.25-5.30 (m, 1H,H-4′); 6.15-6.20 (m, 1H, H-1′), 7.10-7.35 (m, 11H, H arom. and H-5);7.90-7.95 (m, 1H, H-6).

(±)-4-[5-[6-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-hexylamino]-pentanoylamino]-1-[2-[5-[6-(N′-tert-butoxycarbonyl-N′-phenylmethyl-amino)-N-tert-butoxycarbonyl-hexylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 45)

(R₃=H, q=1, n=6, r=1, m=4, R₁=R₂=BOC) from 10e (method A) which wasdirectly used in the subsequent reaction.

(±)-4-[6-[3-(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-propylamino]-hexanoylamino]-1-[2-[6-[3-(N′-tert-butoxycarbonyl-N′-phenylmethyl-amino)-N-tert-butoxycarbonyl-propylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 46)

(R₃=H, q=1, n=3, r=1, m=5, R₁=R₂=BOC) from 10f (method A) which wasdirectly used in the subsequent reaction.

(±)-4-[5-[5(N′-tert-Butoxycarbonyl-N′-phenylmethylamino)-N-tert-butoxycarbonyl-pentylamino]-pentanoylamino]-1-[2-[5-[5-(N′-tert-butoxycarbonyl-N′-phenylmethyl-amino)-N-tert-butoxycarbonyl-pentylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 47)

(R₃=H, q=1, n=5, r=1, m=4, R₁=R₂=BOC) from 10d (method A) which wasdirectly used in the subsequent reaction.

EXAMPLE 2B

Preparation of the compounds of formula (I) wherein R₁═R₂═H

To a solution of 1 equivalent of a compound of formula (I) wherein R₁and R₂ are different from H, prepared as described in example 1B, inCH₂Cl₂ 20 equivalents of CF₃COOH were added.

The resultant mixture was kept under stirring at room temperature up tothe disappearance of the starting compound by TLC (about 2 hours). Afterevaporation of the solvent, the residue was washed with hexane andpurified by preparative thin layer chromatography.

The following compounds of formula (I) were obtained:

Compounds of formula I-A

(±)-4-Amino-1-[2-[6-[5-(phenylmethylamino)pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 48)

(R₃=H, q=1, n=5, r=1, m=5) from Compound 1.

¹H-NMR (CD₃OD): 1.09-1.67 (m, 12H, 6CH₂); 2.09 (t, 2H, J=7.1 Hz, CH₂CO);2.62-2.75 (m, 6H, CH₂N); 2.95-3.07 (m, 3H, 2NH and H-2′a or H-2′b);3.23-3.32 (m, 1H, H-2′a or H-2′b); 3.86 (s, 2H, CH₂Ph); 4.02-4.10 (m,1H, H-5′a or H-5′b); 2H-5′); 4.25-4.34 (m, 1H, H-5′a or H-5′b); 5.12(pseudo q, 1H, H-4′); 5.81 (d, 1H, J=7.9 Hz, H-5); 5.96 (pseudo q, 1H,H-1′); 7.08-7.18 (m, 5H, H arom.); 7.84 (d, 1H, J=7.9 Hz, H-6).

(±)-4-Amino-1-[2-[5-[6-(phenylmethylamino)hexylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 49)

(R₃=H, q=1, n=6, r=1, m=4) from Compound 20

(±)-4-Amino-1-[2-[5-[5-(phenylmethylamino)pentylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 50)

(R₃=H, q=1, n=5, r=1, m=4) from Compound 15

(±)-4-Amino-1-[2-[6-[6-(phenylmethylamino)hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 51)

(R₃=H, q=1, n=6, r=1, m=5) from Compound 3

¹H-NMR (CD₃OD): 1.21-1.89 (m, 14H, 7CH₂); 2.31 (t, 2H, J=6.9 Hz, CH₂CO);2.74-2.86 (m, 6H, 3CH₂N); 3.05-3.10 (m, 1H, H-2′a or H-2′b), 3.38-3.47(m, 1H, H-2′a or H-2′b); 3.66-3.89 (m, 2H, 2H-5′); 3.97 (s, 2H, CH₂Ph);5.13 (t, 1H, J=3.2 Hz, H-4′); 6.09 (pseudo d, 1H, H-1′); 7.02-7.27 (m,6H, H-5 and H arom.); 8.55 (d, 1H, J=7.5 Hz, H-6).

(±)-4-Amino-1-[2-[6-(phenylmethylamino)hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 52)

(R₃=H, q=1, n=5, r=0) from Compound 4

(±)-4-Amino-1-[2-[6-[(3trifluorophenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 53)

(R₃=3-CF₃, q=1, n=5, r=0) from Compound 6

¹H-NMR (CD₃OD): 1.28-1.81 (m, 6H, 3CH₂); 2.42 (t, 2H, J=7.1 Hz, CH₂CO);3.28-3.64 (m, 4H, CH₂N and 2H-2′); 4.29-4.43 (m, 3H, CH₂Ph and H-5′a orH-5′b); 4.58-4.67 (m, 1H, H-5′a or H-5′b); 5.43-5.46 (m, 1H, H-4′); 6.12(d, 1H, J=7.8 Hz, H-5); 6.28-6.32 (m, 1H, H-1′); 7.52-7.85 (m, 4H, Harom.); 8.15 (d, 1H, J=7.8 Hz, H-6).

(±)-4-Amino-1-[2-[6-[6-[(2-trifluoromethylphenyl)methylamino]-hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 54)

(R₃=2-CF₃, q=1, n=6, r=1, m=5) from Compound 8

¹H-NMR (CD₃OD): 1.19-1.61 (m, 14H, 7CH₂); 2.31 (t, 2H, J=7.1 Hz, CH₂CO);2.84-3.25 (m, 7H, 3CH₂N and H-2′a or H-2′b); 3.44-3.52 (m, 1H, H-2′a orH-2′b); 4.24-4.32 (m, 3H, CH₂Ph and H-5′a or H-5′b); 4.46-4.55 (m, 1H,H-5′a or H-5′b); 5.34 (q, 1H, J₁=3.3 Hz, J₂=5.4 Hz, H-4′); 6.18 (bs, 1H,H-5); 6.20 (m, 1H, H-1′); 7.50-7.75 (m, 4H, H arom.); 7.98 (d, 1H, J=7.7Hz, H-6).

(±)-4-Amino-1-[2-[6-[(2-trifluorophenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 55)

(R₃=2-CF₃, q=1, n=5, r=0) from Compound 7

¹H-NMR (CD₃OD): 1.17-1.73 (m, 6H, 3CH₂); 2.32 (t, 2H, J=7.1 Hz, CH₂CO);3.00-3.54 (m, 4H, CH₂N and 2H-2′); 4.24-4.32 (m, 3H, CH₂Ph and H-5′a orH-5′b); 4.47-4.56 (m, 1H, H-5′a or H-5′b); 5.34 (q, 1H, J₁=3.4 Hz,J₂=5.4 Hz, H-4′); 6.17 (bs, 1H, H-5); 6.20 (pseudo q, 1H, H-1′);7.49-7.74 (m, 4H, H arom.); 8.04 (d, 1H, J=7.8 Hz, H-6).

Compounds of formula I-B

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[6-phenylmethylamino)hexylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 56)

(R₃=H, q=1, n=6, r=1, m=5) from Compound 25

¹H-NMR (CD₃OD): 1.18-1.82 (m, 14H, 7CH₂); 2.24-2.55 (m, 2H, CH₂CO);2.82-2.98 (m, 6H, 3CH₂N); 3.10-3.22 (m, 1H, H-2′a or H-2′b); 4.09 (s,2H, CH₂Ph); 4.33-4.39 (m, 1H, H-5′a or H-5′b); 4.51-4.60 (m, 1H, H-5′aor H-5′b); 5.38 (pseudo d, 1H, H-4′); 6.20 (pseudo d, 1H, H-1′);7.14-7.40 (m, 6H, H-5 and H arom.); 8.22 (d, 1H, J=7.5 Hz, H-6).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[5-(phenylmethylamino)pentylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 57)

(R₃=H, q=1, n=5, r=1, m=5) from Compound 23

Rf=0.30 (CH₂Cl₂:CH₃OH=8:2)

¹H-NMR (CD₃OD): 1.20-1.61 (m, 12H, 6CH₂); 2.30 (t, 2H, J=7.1 Hz, CH₂CO);2.73-2.86 (m, 6H, 3CH₂N); 3.03-3.10 (m, 3H, 2NH and H-2′a or H-2′b);3.37-3.46 (m, 1H, H-2′a or H-2′b); 3.66-3.86 (m, 2H, 2H-5′); 3.97 (s,2H, CH₂Ph); 5.12 (t, 1H, J=3.2 Hz, H-4′); 6.08 (pseudo q, 1H, H-1′),7.00 (d, 1H, J=3.2 Hz, H-5); 7.19-7.29 (m, 5H, H arom.); 8.53 (d, 1H,J=7.5 Hz, H-6).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[5-[6-(phenylmethylamino)hexylamino]-pentanoylamino]-2(1H)-pyrimidinone(Compound 58)

(R₃=H, q=1, n=6, r=1, m=4) from Compound 32

Rf=0.1 (CH₂Cl₂:CH₃OH=9:1)

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[3-(phenylmethylamino)propylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 59)

(R₃=H, q=1, n=3, r=1, m=5) from Compound 33

¹H-NMR (CD₃OD): 1.30-1.80 (m, 35H, 4CH₂); 2.40-2.48 (m, 2H, 2CH₂CO);2.60-2.74 (m, 6H, 3CH₂N); 3.19-3.66 (m, 2H, 2H-2′); 3.74 (bs, 2H,CH₂Ph); 3.86-4.07 (m, 2H, 2H-5′); 5.31-5.35 (m, 1H, H-4′); 6.27-6.31 (m,1H, H-1′); 7.20-7.35 (m, 5H, H arom.); 7.42 (d, 1H, J=7.5 Hz, H-5); 8.57(d, 1H, J=7.5 Hz, H-6).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[5-[5-(phenylmethylamino)pentylamino]-pentanoylamino]-2(1H)-pyrimidinone(Compound 60)

(R₃=H, q=1, n=5, r=1, m=4) from Compound 34

(±)-1-(2Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[4-(phenylmethylamino)butylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 61)

(R₃=H, q=1, n=4, r=1, m=5) from Compound 24

¹H-NMR (CD₃OD): 1.25-1.85 (m, 10H, 5CH₂); 2.40-2.60 (m, 2H, CH₂CO);2.80-3.10 (bs, 7H, 3CH₂N and H-2′a or H-2′b); 3.20-3.30 (m, 1H, H-2′a orH-2′b); 3.60-3.80 (m, 2H, 2H-5′); 4.20 (bs, 2H, CH₂Ph); 5.30-5.40(pseudo t, 1H, H-4′); 6.20-6.35 (m, 1H, H-1′); 7.25 (d, 1H, J=7.5 Hz,H-5); 7.40-7.65 (m, 5H, H arom.); 8.05 (d, 1H, J=7.5 Hz, H-6).

(±)-1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)4-[6-[6-[(2-trifluoromethylphenyl)-methylamino]-hexylamino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 62)

(R₃=2-CF₃, q=1, n=6, r=1, m=5) from Compound 26

¹H-NMR (CD₃OD): 1.30-1.57 (m, 14H, 7CH₂); 2.35 (t, 2H, J=6.7 Hz, CH₂CO);2.54-3.17 (m, 7H, 3CH₂N and H-2′a or H-2′b); 3.31-3.53 (m, 1H, H-2′a orH-2′b); 3.72-3.94 (m, 2H, 2H-5′); 4.25 (bs, 2H, CH₂Ph); 5.19 (t, 1H,J=3.4 Hz, H-4′); 6.15 (q, 1H, J₁=2.4 Hz, J₂=5.0 Hz, H-1′); 7.17 (bs, 1H,H-5); 7.45-7.70 (m, 4H, H arom.); 8.50 (d, 1H, J=7.5 Hz, H-6).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-(phenylmethylamino)hexanoylamino]-2(1H)-pyrimidinone(Compound 63)

(R₃=H, q=1, n=5, r=0) from Compound 27

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[(3trifluoromethylphenyl)methyl-amino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 64)

(R₃=3-CF₃, q=1, n=5, r=0) from Compound 28

¹H-NMR (CD₃OD): 1.22-1.84 (m, 6H, 3CH₂); 2.49 (t, 2H, J=7.0 Hz, CH₂CO);3.08-3.53 (m, 2H, CH₂N); 3.58-3.73 (m, 1H, H-2′a or H-2′b); 3.87-4.10(m, 1H, H-2′a or H-2′b); 4.31-4.42 (m, 3H, CH₂Ph and H-5′a or H-5′b);4.82-4.89 (m, 1H, H-5′a or H-5′b); 5.32-5.35 (t, 1H, H-4′); 6.26-6.30(m, 1H, H-1′); 7.24-7.85 (m, 5H, H-5, H arom.); 8.63 (d, 1H, J=7.5 Hz,H-6).

(±)1-(2-Hydroxymethyl-1,3-oxathiolan-5-yl)-4-[6-[(2-trifluoromethylphenyl)methyl-amino]-hexanoylamino]-2(1H)-pyrimidinone(Compound 65)

(R₃=2-CF₃, q=1, n=5, r=0) from Compound 29

¹H-NMR (CD₃OD): 1.17-1.64 (m, 6H, 3CH₂); 2.41 (bs, 2H, CH₂CO); 3.02-3.19(m, 3H, CH₂N, H-2′a or H-2′b); 3.50-3.54 (m, 1H, H-2′a or H-2′b);3.76-3.97 (m, 2H, 2H-5′); 4.29 (m, 2H, CH₂Ph); 5.23 (t, 1H, J=3.2 Hz,H-4′); 6.19 (bs, 1H, H-1′); 7.49-7.74 (m, 5H, H-5, H arom.); 8.54 (d,1H, J=6.6 Hz, H-6).

Compounds of formula I-C

(±)-4-[6-[5-(Phenylmethylamino)pentylamino]-hexanoylamino]-1-[2-[6-[5-(phenylmethylamino)pentylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 66)

(R₃=H, q=1, n=5, r=1, m=5) from Compound 37

¹H-NMR (CD₃OD): 1.15-1.55 (m, 24H, 12CH₂); 2.06-2.27 (m, 4H, CH₂CO);2.63-2.80 (m, 12H, 6CH₂N); 3.00-3.10 (m, 1H, H-2′a or H-2′b); 3.30-3.50(m, 1H, H-2′a or H-2′b); 3.91 (s, 4H, CH₂Ph); 4.13-4.38 (m, 2H, 2H-5′);5.20 (pseudo q, 1H, H-4′); 6.02 (pseudo d, 1H, H-1′); 7.12-7.23 (m, 11H,H-5, H arom.); 8.09 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[5-[6-(Phenylmethylamino)hexylamino]-pentanoylamino]-1-[2-[5-[6-(phenylmethylamino)hexylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 67)

(R₃=H, q=1, n=6, r=1, m=4) from Compound 45

(±)-4-[6-[6-(Phenylmethylamino)hexylamino]-hexanoylamino]-1-[2-[6-[6-(phenylmethylamino)hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 68)

(R₃=H, q=1, n=6, r=1, m=5) from Compound 36

¹H-NMR (CD₃OD): 1.18-1.88 (m, 28H, 14CH₂); 2.26-2.43 (m, 4H, 2CH₂CO);2.84-2.97 (m, 12H, 6CH₂N); 3.16-3.20 (m, 1H, H-2′a or H-2′b); 3.51-3.60(m, 1H, H-2′a or H-2′b); 4.09 (s, 4H, 2CH₂Ph); 4.30-4.37 (m, 1H, H-5′aor H-5′b); 4.52-4.61 (m, 1H, H-5′a or H-5′b); 5.38 (pseudo d, 1H, H-4′);6.21 (pseudo d, 1H, H-1′); 7.32-7.40 (m, 11H, H-5, H arom.); 8.20 (d,1H, J=7.5 Hz, H-6).

(±)-4-[5-[5-(Phenylmethylamino)pentylamino]-pentanoylamino]-1-[2-[5-[5-(phenylmethylamino)pentylamino]-pentanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 69)

(R₃=H, q=1, n=5, r=1, m=4) from Compound 47

Rf=0.5 (AcOEt)

(±)-4-[6-[3-(Phenylmethylamino)propylamino]-hexanoylamino]1-[2-[6-[3-(phenylmethylamino)propylamino]-hexanoyloxymethyl-]1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 70)

(R₃=H, q=1, n=3, r=1, m=5) from Compound 46

¹H-NMR (CD₃OD): 1.25-1.75 (m, 16H, 8CH₂); 2.30-2.50 (m, 4H, 2CH₂CO);2.85-3.15 (m, 7H, 3CH₂N and H-2′a or H-2′b); 3.50-3.65 (m, 1H, H-2′a orH-2′b); 4.10 (bs, 4H, 2CH₂Ph); 4.25-4.60 (m, 2H, 2H-5′); 5.35-5.45 (m,1H; H-4′); 6.20-6.30 (m, 1H, H-1′); 7.30-7.45 (m, 11H, H-5, H arom.);8.25 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[6-[4-(Phenylmethylamino)butylamino]-hexanoylamino]-1-[2-[6-[4-(phenylmethylamino)butylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 71)

(R₃=H, q=1, n=4, r=1, m=5) from Compound 38

¹H-NMR (DMSO-d₆): 1.10-1.70 (m, 20H, 10CH₂); 2.20-2.45 (m, 4H, 2CH₂CO);3.10-3.55 (m, 14H, 6CH₂N and 2H-2′); 3.85-4.15 (m, 3H, CH₂Ph and H-5′aor H-5′b); 4.25-4.45(m, 1H, H-5′a or H-5′b); 5.25-5.30 (m, 1H, H-4′);6.05-6.18 (m, 1H, H-1′); 7.10 (d, 1H, J=7.5 Hz, H-5); 7.20-7.45 (m, 10H,H arom.); 8.05 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[6-(Phenylmethylamino)hexanoylamino]-1-[2-[6-(phenylmethylamino)hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 72)

(R₃=H, q=1, n=5, r=0) from Compound 39

¹H-NMR (CD₃OD): 1.28-1.72 (m, 6H, 3CH₂); 2.40-2.50 (t, 2H, J=6.9 Hz,CH₂CO); 2.91-3.28 (m, 3H, CH₂N and H-2′a or H-2′b); 3.53-3.69 (m, 1H,H-2′a or H-2′b); 4.19 (bs, 2H, CH₂Ph); 4.35-4.70 (m, 2H, 2H-5′);5.46-5.50 (m, 1H, H-4′); 6.27 (pseudo q, 1H, H-1′); 7.44 (bs, 10H).

(±)-4-[6-[(3-Trifluoromethylphenyl)methylamino]-hexanoylamino]-1-[2-[6-[(3-trifluoromethylphenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 73)

(R₃=3-CF₃, q=1, n=5, r=0) from Compound 40

¹H-NMR (CD₃OD): 1.32-1.73 (m, 12H, 6CH₂); 2.44-2.51 (m, 4H, CH₂CO);3.05-3.31 (m, 5H, 2CH₂N and H-2′a or H-2′b); 3.61-3.69 (m, 1H, H-2′a orH-2′b); 4.29-4.49 (m, 5H, 2CH₂Ph and H-5′a or H-5′b); 4.61-4.70 (m, 1H,H-5′a or H-5′b); 5.48 (m, 1H, H-4′); 6.30 (m, 1H, H-1′); 7.39-7.86 (m,9H, H arom. and H-5); 8.29 (d, 1H, J=7.5 Hz, H-6).

(±)-4-[6-[6-[(2-Trifluoromethylphenyl)methylamino]-hexylamino]-hexanoylamino]-1-[[2-[6-[6-(2-trifluoromethylphenyl)methylamino]-hexylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 74)

(R₃=2-CF₃, q=1, n=6, r=1, m=5) from Compound 42

¹H-NMR (CD₃OD):1.17-1.58 (m, 28H, 14CH₂); 2.25-2.35 (m, 4H, 2CH₂CO);2.80-3.17 (m, 13H, 6CH₂N and H-2′a or H-2′b); 3.46-3.55 (m, 1H, H-2′a orH-2′b); 4.25-4.33 (m, 5H, 2CH₂Ph and H-5′a or H-5′b); 4.47-4.56 (m, 1H,H-5′a or H-5′b); 5.33 (q, 1H, J₁=3.2 Hz, J₂=4.8 Hz, H-4′); 6.16 (bs, 1H,H-1′); 7.45-7.70 (m, 9H, H arom. and H-5); 8.16 (d, 1H, J=7.4 Hz, H-6).

(±)-4-[6-[(2-Trifluoromethylphenyl)methylamino]-hexanoylamino]-1-[2-[6-[(2-trifluoromethylphenyl)methylamino]-hexanoyloxymethyl]-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone(Compound 75)

(R₃=2-CF₃, q=1, n=5, r=0) from Compound 41

¹H-NMR (CD₃OD): 1.16-1.65 (m, 12H, 6CH₂); 2.28-2.47 (m, 4H, 2CH₂CO);3.04-3.20 (m, 6H, 2CH₂N and 2H-2′); 4.28-4.34 (m, 5H, 2CH₂Ph and H-5′aor H-5′b); 4.47-4.56 (m, 1H, H-5′a or H-5′b); 5.39 (bs, 1H, H-4′); 6.20(bs, 1H, H-1′); 7.52-7.73 (m, 9H, H arom. and H-5); 8.38 (bs, 1H, H-6).

Part C—Pharmacologic Activity EXAMPLE 1C

Anti-HIV activity

The anti-HIV activity of the compounds of formula I was evaluated on thelimphocitic human cell line MT4 infected by HIV-1 strain BRU and onfresh human macrophages infected by the macrophage-trophic HIV- 1 PARstrain.

Lymphocytes (MT4 cells)

The cells, infected and treated with the compounds of formula I, werecultured at 37° C. for 7-8 days. Every 3-4 days the culture supernatantwas withdrawn and substituted with fresh medium containing or not thecompounds of formula I. The anti-HIV activity was evaluated at the endof the experiment as 50% inhibition (IC₅₀) of the activity of the viralreverse transcriptase in the supernatant of infected cultures incomparison with the control cultures.

The used methodologies were described in the papers published by Rey M.A. et al. on Biochem. Biophys. Res. Commun. (1984), 121, 126-133 and onVirology (1991), 181, 165-171.

Macrophages

The cells, infected and treated with the compounds of formula I, werecultured at 37° C. for about 1 month. Every 3-4 days the culturesupernatant was withdrawn and substituted with fresh medium containingor not the compounds of formula I. The viral reverse-transcriptaseactivity, determined in the culture supernatant every 3-4 days, wasfollowed up to the end of the experiment by determining the maximum peakof the enzyme expression. In the correspondence of such a peak theanti-HIV activity was evaluated as 50% inhibition (IC₅₀) of theenzymatic activity in the supernatant of the infected and treatedcultures in comparison with the control ones.

The used methodology was described by Schmidtmayerova H. et al. onVirology (1992), 190, 124-133.

In the following table the data of anti-HIV activity on both the celllines for some representative compounds of formula I are reported.

Lymphocytes Macrophages Compound IC₅₀ (μM) IC₅₀ (μM) 56 0.13 0.1 57 0.410.1 1 0.001-0.005 <10⁻⁵ 4 0.001 6 0.004 7 0.001-0.01 54 0.8 48 0.15 520.1-1 53 0.7 55 0.1 9 0.001-0.05 49 0.9 10 0.01-0.1 2 <0.1 8 0.1 BCH-1890.7 0.1

What is claimed is:
 1. A compound of formula

wherein R_(a) and R_(b) are the same or different and are selected fromthe group consisting of hydrogen, acyl group derived from a lowercarboxylic acid or chains of the formula

wherein R is a group of formula

wherein R₃ is selected from the group consisting of hydrogen, halogen,trifluoromethyl and C₁-C₃ alkoxy; R₁ and R₂ are the same or differentand are selected from the group consisting of hydrogen,phenylalkoxycarbonyl having 1 to 3 carbon atoms in the alkoxy moiety,C₂-C₆ alkoxycarbonyl and C₂-C₆ alkylcarbonyl; W is selected from thegroup consisting of a single bond, an oxygen atom and a group —CH(Alk)—,wherein Alk is a linear or branched C₁-C₃ alkyl group; r is 0 or 1,wherein when r is 0, n is 1 to 6, and when r is 1, n is 2 to 7; and m is2 to 7, provided that at least one of R_(a) and R_(b) is other than ahydrogen atom or an acyl group derived from a lower carboxylic acid. 2.A compound according to claim 1 of formula

wherein R, R₁, R₂, W, n, m and r have the meanings reported in claim 1and R′_(b) is a hydrogen atom or an acyl group deriving from a lowercarboxylic acid.
 3. A compound according to claim 1 of formula

wherein R, R₁, R₂, W, n, m and r have the meanings reported in claim 1and R′_(a) is a hydrogen atom or an acyl group deriving from a lowercarboxylic acid.
 4. A compound according to claim 1 of formula

wherein R, R₁, R₂, W, n, m and r have the meanings reported in claim 1.5. A compound according to claim 1 having the (2R,5S) configuration oflamivudine.
 6. A compound according to claim 1 wherein R₁ and R₂ areC₂-C₆ alkoxycarbonyl groups.
 7. A compound according to claim 6 whereinR₁ and R₂ are tert-butoxycarbonyl groups.
 8. A compound according toclaim 1 wherein W is a single bond and R₃ is a hydrogen atom or atrifluoromethyl group.
 9. A compound according to claim 8 wherein n is 4to 6 and m is 4 to
 5. 10. A compound according to claim 1 wherein R₁ andR₂ are other than hydrogen.
 11. A process for the preparation of thecompounds according to claim 1 comprising the acylation of lamivudine

by reaction with a compound of formula

wherein R, R₁, R₂, n, m and W have the meanings reported in claim 1 andR₄ is an OH group or a suitable leaving group when W is different fromoxygen or R₄ is a suitable leaving group when W is oxygen.
 12. Apharmaceutical composition containing one or more compounds according toclaim 1 in admixture with a pharmaceutically acceptable carrier.